Skip to main content

Advertisement

Log in

Opioid System and Alzheimer’s Disease

  • Review Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

The opioid system may be involved in the pathogenesis of AD, including cognitive impairment, hyperphosphorylated tau, Aβ production, and neuroinflammation. Opioid receptors influence the regulation of neurotransmitters such as acetylcholine, norepinephrine, GABA, glutamate, and serotonin which have been implicated in the pathogenesis of AD. Opioid system has a close relation with Aβ generation since dysfunction of opioid receptors retards the endocytosis and degradation of BACE1 and γ-secretase and upregulates BACE1 and γ-secretase, and subsequently, the production of Aβ. Conversely, activation of opioid receptors increases the endocytosis of BACE1 and γ-secretase and downregulates BACE1 and γ-secretase, limiting the production of Aβ. The dysfunction of opioid system (opioid receptors and opioid peptides) may contribute to hyperphosphorylation of tau and neuroinflammation, and accounts for the degeneration of cholinergic neurons and cognitive impairment. Thus, the opioid system is potentially related to AD pathology and may be a very attractive drug target for novel pharmacotherapies of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

Aβ:

Beta-amyloid

ACTH:

Adrenocorticotropin hormone

AD:

Alzheimer’s disease

ADAMS:

Aging, Demographics, and Memory Study

APP:

Amyloid precursor protein

BACE:

Beta-site APP-cleaving enzyme

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

DOR:

Delta-opioid receptor

DAGO:

Tyr-D-Ala-Gly- (Me) Phe-Gly-ol

DADPE:

D-Ala2, D-Leu5 enkephalin

DSLET:

D-Ser2, Thr6 Leu5 enkephalin

GABA:

Gamma aminobutyric acid

KOR:

Kappa-opioid receptor

LC:

Locus ceruleus

LPH:

α, β, and γ-Lipotropin

LTP:

Long-term potentiation

MDMA:

3,4-Methylenedioxymethamphetamine

MEK:

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase

MSH:

α- and β-Melanotropin

MOR:

Mu-opioid receptor

NMDA:

N-methyl-d-aspartate

NOP:

Nociceptin receptor

NFT:

Neurofibrillary tangles

OR:

Opioid receptor

OGFr:

Opioid growth factor receptor

ORL1:

Opioid receptor-like receptor

PHF:

Paired helical

PI3K:

Phosphatidilinositol-3 kinase

PNOC:

Prepronociceptin PNS: peripheral nervous system

PET:

Positron Emission Tomography

SPECT:

Single Photon Emission Computed Tomography

References

  • Ahmed, M. S., & Horst, M. A. (1986). Opioid receptors of human placental villi modulate acetylcholine release. Life Sciences, 39, 535–540.

    Article  PubMed  CAS  Google Scholar 

  • Ahmed, M. S., Schoof, T., Zhou, D. H., & Quarles, C. (1989). Kappa opioid receptors of human placental villi modulate acetylcholine release. Life Sciences, 45, 2383–2393.

    Article  PubMed  CAS  Google Scholar 

  • Akuzawa, N., Takeda, S., & Ishiguro, M. (2007). Structural modelling and mutation analysis of a nociceptin receptor and its ligand complexes. Journal of Biochemistry, 141, 907–916.

    Article  PubMed  CAS  Google Scholar 

  • Alfaras-Melainis, K., Gomes, I., Rozenfeld, R., Zachariou, V., & Devi, L. (2009). Modulation of opioid receptor function by protein–protein interactions. Frontiers in Bioscience, 14, 3594–3607.

    Article  PubMed  CAS  Google Scholar 

  • Anthony, I. C., Norrby, K. E., Dingwall, T., Carnie, F. W., Millar, T., Arango, J. C., et al. (2010). Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers. Brain, 133, 3685–3698.

    Article  PubMed  Google Scholar 

  • Antonini, V., Marrazzo, A., Kleiner, G., Coradazzi, M., Ronsisvalle, S., Prezzavento, O., et al. (2011). Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. Journal of Alzheimers Disease, 24, 569–586.

    CAS  Google Scholar 

  • Arendt, T. (2004). Neurodegeneration and plasticity. International Journal of Developmental Neuroscience, 22, 507–514.

    Article  PubMed  CAS  Google Scholar 

  • Avella, D. M., Kimchi, E. T., Donahue, R. N., Tagaram, H. R., McLaughlin, P. J., Zagon, I. S., et al. (2010). The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 298, R459–R466.

    Article  PubMed  CAS  Google Scholar 

  • Bagetta, G., De Sarro, G. B., Sakurada, S., Rispoli, V., & Nistico, G. (1990). Different profile of electrocortical power spectrum changes after micro-infusion into the locus coeruleus of selective agonists at various opioid receptor subtypes in rats. British Journal of Pharmacology, 101, 655–661.

    PubMed  CAS  Google Scholar 

  • Bales, K. R., Tzavara, E. T., Wu, S., Wade, M. R., Bymaster, F. P., Paul, S. M., et al. (2006). Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. The Journal of Clinical Investigation, 116, 825–832.

    Article  PubMed  CAS  Google Scholar 

  • Barber, A. (1993). Mu- and kappa-opioid receptor agonists produce peripheral inhibition of neurogenic plasma extravasation in rat skin. European Journal of Pharmacology, 236, 113–120.

    Article  PubMed  CAS  Google Scholar 

  • Barg, J., Belcheva, M., Rowinski, J., Ho, A., Burke, W. J., Chung, H. D., et al. (1993). Opioid receptor density changes in Alzheimer amygdala and putamen. Brain Research, 632, 209–215.

    Article  PubMed  CAS  Google Scholar 

  • Bartsch, T., Akerman, S., & Goadsby, P. J. (2002). The ORL-1 (NOP1) receptor ligand nociceptin/orphanin FQ (N/OFQ) inhibits neurogenic dural vasodilatation in the rat. Neuropharmacology, 43, 991–998.

    Article  PubMed  CAS  Google Scholar 

  • Baum, L., Masliah, E., Iimoto, D. S., Hansen, L. A., Halliday, W. C., & Saitoh, T. (1992). Casein kinase II is associated with neurofibrillary tangles but is not an intrinsic component of paired helical filaments. Brain Research, 573, 126–132.

    Article  PubMed  CAS  Google Scholar 

  • Benamar, K., Yondorf, M., Barreto, V. T., Geller, E. B., & Adler, M. W. (2007). Deletion of mu-opioid receptor in mice alters the development of acute neuroinflammation. Journal of Pharmacology and Experimental Therapeutics, 323, 990–994.

    Article  PubMed  CAS  Google Scholar 

  • Bergstrom, J., Ahmed, M., Li, J., Ahmad, T., Kreicbergs, A., & Spetea, M. (2006). Opioid peptides and receptors in joint tissues: Study in the rat. Journal of Orthopaedic Research, 24, 1193–1199.

    Article  PubMed  CAS  Google Scholar 

  • Bhalla, S., Zhang, Z., Patterson, N., & Gulati, A. (2010). Effect of endothelin-A receptor antagonist on mu, delta and kappa opioid receptor-mediated antinociception in mice. European Journal of Pharmacology, 635, 62–71.

    Article  PubMed  CAS  Google Scholar 

  • Birkas, E., Bakota, L., Gulya, K., Wen, T., Pintar, J., Toth, G., et al. (2011). A comprehensive study on the putative delta-opioid receptor (sub)types using the highly selective delta-antagonist, Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH. Neurochemistry International, 59, 192–201.

    Article  PubMed  CAS  Google Scholar 

  • Blake, A. D., Bot, G., Tallent, M., Law, S. F., Li, S., Freeman, J. C., et al. (1997). Molecular regulation of opioid receptors. Receptors and Channels, 5, 231–235.

    PubMed  CAS  Google Scholar 

  • Blebea, J., Mazo, J. E., Kihara, T. K., Vu, J. H., McLaughlin, P. J., Atnip, R. G., et al. (2000). Opioid growth factor modulates angiogenesis. Journal of Vascular Surgery, 32, 364–373.

    Article  PubMed  CAS  Google Scholar 

  • Boddeke, H. W., Meigel, I., Swoboda, R., & Boeijinga, P. H. (1994). The amyloid precursor protein fragment His 657-Lys 676 inhibits noradrenaline- and enkephaline-induced suppression of voltage sensitive calcium currents in NG108-15 hybrid cells. Neuroscience, 62, 631–634.

    Article  PubMed  CAS  Google Scholar 

  • Bot, N., Schweizer, C., Ben Halima, S., & Fraering, P. C. (2011). Processing of the synaptic cell adhesion molecule neurexin-3beta by Alzheimer disease alpha- and gamma-secretases. Journal of Biological Chemistry, 286, 2762–2773.

    Article  PubMed  CAS  Google Scholar 

  • Brion, J. P., Anderton, B. H., Authelet, M., Dayanandan, R., Leroy, K., Lovestone, S., et al. (2001). Neurofibrillary tangles and tau phosphorylation. Biochemical Society Symposium, 81–88.

  • Bruijnzeel, A. W. (2009). kappa-Opioid receptor signaling and brain reward function. Brain Research Reviews, 62, 127–146.

    Article  PubMed  CAS  Google Scholar 

  • Brunden, K. R., Trojanowski, J. Q., & Lee, V. M. (2009). Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nature Reviews Drug Discovery, 8, 783–793.

    Article  PubMed  CAS  Google Scholar 

  • Buoso, E., Lanni, C., Schettini, G., Govoni, S., & Racchi, M. (2010). beta-Amyloid precursor protein metabolism: Focus on the functions and degradation of its intracellular domain. Pharmacological Research, 62, 308–317.

    Article  PubMed  CAS  Google Scholar 

  • Burchinsky, S. G. (1984). Neurotransmitter receptors in the central nervous system and aging: Pharmacological aspect (review). Experimental Gerontology, 19, 227–239.

    Article  PubMed  CAS  Google Scholar 

  • Callahan, P., & Pasternak, G. W. (1987). Opiates, opioid peptides, and their receptors. Journal of Cardiothoracic Anesthesia, 1, 569–576.

    Article  PubMed  CAS  Google Scholar 

  • Candore, G., Bulati, M., Caruso, C., Castiglia, L., Colonna-Romano, G., Di Bona, D., et al. (2010). Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: Therapeutic implications. Rejuvenation Research, 13, 301–313.

    Article  PubMed  CAS  Google Scholar 

  • Caraci, F., Molinaro, G., Battaglia, G., Giuffrida, M. L., Riozzi, B., Traficante, A., et al. (2011). Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer’s disease: Selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Molecular Pharmacology, 79, 618–626.

    Article  PubMed  CAS  Google Scholar 

  • Carr, J. A., & Gregg, K. J. (1995). Opioid peptide inhibition of endogenous norepinephrine release from the A2 noradrenergic cell group in vitro. Neuropeptides, 28, 219–225.

    Article  PubMed  CAS  Google Scholar 

  • Casamenti, F., Prosperi, C., Scali, C., Giovannelli, L., Colivicchi, M. A., Faussone-Pellegrini, M. S., et al. (1999). Interleukin-1beta activates forebrain glial cells and increases nitric oxide production and cortical glutamate and GABA release in vivo: Implications for Alzheimer’s disease. Neuroscience, 91, 831–842.

    Article  PubMed  CAS  Google Scholar 

  • Cerpa-Poljak, A., Lahnstein, J., Mason, K. E., Smythe, G. A., & Duncan, M. W. (1997). Mass spectrometric identification and quantification of hemorphins extracted from human adrenal and pheochromocytoma tissue. Journal of Neurochemistry, 68, 1712–1719.

    Article  PubMed  CAS  Google Scholar 

  • Cesselin, F. (1991). Endorphins, opioid receptors and site of action of morphinomimetics. Agressologie, 32, 310–317.

    PubMed  CAS  Google Scholar 

  • Champion, H. C., Pierce, R. L., & Kadowitz, P. J. (1998). Nociceptin, a novel endogenous ligand for the ORL1 receptor, dilates isolated resistance arteries from the rat. Regulatory Peptides, 78, 69–74.

    Article  PubMed  CAS  Google Scholar 

  • Chandrakumar, N. S., Stapelfeld, A., Beardsley, P. M., Lopez, O. T., Drury, B., Anthony, E., et al. (1992). Analogs of the delta opioid receptor selective cyclic peptide [2-D-penicillamine,5-D-penicillamine]-enkephalin: 2′,6′-dimethyltyrosine and Gly3-Phe4 amide bond isostere substitutions. Journal of Medicinal Chemistry, 35, 2928–2938.

    Article  PubMed  CAS  Google Scholar 

  • Chapman, I. M., & Willoughby, J. O. (1993). Interactions between the effects of opioid, serotonin and alpha-2-adrenergic receptor agonists on growth hormone release in the male rat. Intravenous administration. Neuroendocrinology, 57, 912–920.

    Article  PubMed  CAS  Google Scholar 

  • Chaturvedi, K. (2003). Opioid peptides, opioid receptors and mechanism of down regulation. Indian Journal of Experimental Biology, 41, 5–13.

    PubMed  CAS  Google Scholar 

  • Chavkin, C., McLaughlin, J. P., & Celver, J. P. (2001). Regulation of opioid receptor function by chronic agonist exposure: Constitutive activity and desensitization. Molecular Pharmacology, 60, 20–25.

    PubMed  CAS  Google Scholar 

  • Christov, A., Ottman, J. T., & Grammas, P. (2004). Vascular inflammatory, oxidative and protease-based processes: Implications for neuronal cell death in Alzheimer’s disease. Neurological Research, 26, 540–546.

    Article  PubMed  CAS  Google Scholar 

  • Chu, D. C., Penney, J. B., Jr, & Young, A. B. (1987). Quantitative autoradiography of hippocampal GABAB and GABAA receptor changes in Alzheimer’s disease. Neuroscience Letters, 82, 246–252.

    Article  PubMed  CAS  Google Scholar 

  • Church, J. (1991). Opioid receptors—the role of the sigma receptor? British Journal of Anaesthesia, 67, 361–362.

    Article  PubMed  CAS  Google Scholar 

  • Clark, W. G., Bernardini, G. L., & Ponder, S. W. (1981). Central injection of a sigma opioid receptor agonist alters body temperature of cats. Brain Research Bulletin, 7, 279–281.

    Article  PubMed  CAS  Google Scholar 

  • Codd, E. E., Yellin, T., & Walker, R. F. (1988). Binding of growth hormone-releasing hormones and enkephalin-derived growth hormone-releasing peptides to mu and delta opioid receptors in forebrain of rat. Neuropharmacology, 27, 1019–1025.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, R. M., Andreason, P. J., Doudet, D. J., Carson, R. E., & Sunderland, T. (1997). Opiate receptor avidity and cerebral blood flow in Alzheimer’s disease. Journal of the Neurological Sciences, 148, 171–180.

    Article  PubMed  CAS  Google Scholar 

  • Collier, T. L., Waterhouse, R. N., & Kassiou, M. (2007). Imaging sigma receptors: Applications in drug development. Current Pharmaceutical Design, 13, 51–72.

    Article  PubMed  CAS  Google Scholar 

  • Conason, A. H., & Sher, L. (2006). Alcohol use in adolescents with eating disorders. International Journal of Adolescent Medicine and health, 18, 31–36.

    Article  PubMed  Google Scholar 

  • Connor, M., Vaughan, C. W., Jennings, E. A., Allen, R. G., & Christie, M. J. (1999). Nociceptin, Phe(1)psi-nociceptin(1 - 13), nocistatin and prepronociceptin(154 - 181) effects on calcium channel currents and a potassium current in rat locus coeruleus in vitro. British Journal of Pharmacology, 128, 1779–1787.

    Article  PubMed  CAS  Google Scholar 

  • Conway, E. L., Brown, M. J., & Dollery, C. T. (1984). No evidence for involvement of endogenous opioid peptides in effects of clonidine on blood pressure, heart rate and plasma norepinephrine in anesthetized rats. Journal of Pharmacology and Experimental Therapeutics, 229, 803–808.

    PubMed  CAS  Google Scholar 

  • Coralli, M. V., Zanotti, E., & Salsi, A. (1986). Current concepts on the hypothesis of the cholinergic etiology of Alzheimer’s disease. Recenti Progressi in Medicina, 77, 436–439.

    PubMed  CAS  Google Scholar 

  • Costentin, J., Florin, S., Suaudeau, C., & Meunier, J. C. (1998). Cloning of prepronociceptin has led to the discovery of other biologically active peptides. Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales, 192, 1099–1109.

    PubMed  CAS  Google Scholar 

  • D’Addario, C., Di Benedetto, M., Izenwasser, S., Candeletti, S., & Romualdi, P. (2007). Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS. Neuroscience, 144, 157–164.

    Article  PubMed  CAS  Google Scholar 

  • Davis, R. L., Buck, D. J., Saffarian, N., Mohan, S., DeSilva, U., Fernando, S. C., et al. (2008). Beta-funaltrexamine inhibits inducible nitric-oxide synthase expression in human astroglial cells. Journal of Neuroimmune Pharmacology, 3, 150–153.

    Article  PubMed  Google Scholar 

  • Davis, R. L., Buck, D. J., Saffarian, N., & Stevens, C. W. (2007). The opioid antagonist, beta-funaltrexamine, inhibits chemokine expression in human astroglial cells. Journal of Neuroimmunology, 186, 141–149.

    Article  PubMed  CAS  Google Scholar 

  • de la Monte, S. M., & Wands, J. R. (2001). Alzheimer-associated neuronal thread protein-induced apoptosis and impaired mitochondrial function in human central nervous system-derived neuronal cells. Journal of Neuropathology and Experimental Neurology, 60, 195–207.

    PubMed  Google Scholar 

  • DeLeo, J. A., Tanga, F. Y., & Tawfik, V. L. (2004). Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist, 10, 40–52.

    Article  PubMed  CAS  Google Scholar 

  • Dhikav, V., & Anand, K. (2011). Potential predictors of hippocampal atrophy in Alzheimer’s disease. Drugs and Aging, 28, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Diamant, M., Henricks, P. A., Nijkamp, F. P., & de Wied, D. (1989). Beta-endorphin and related peptides suppress phorbol myristate acetate-induced respiratory burst in human polymorphonuclear leukocytes. Life Sciences, 45, 1537–1545.

    Article  PubMed  CAS  Google Scholar 

  • Dietl, M. M., Cortes, R., & Palacios, J. M. (1988). Neurotransmitter receptors in the avian brain. III. GABA-benzodiazepine receptors. Brain Research, 439, 366–371.

    Article  PubMed  CAS  Google Scholar 

  • Diez, M., Danner, S., Frey, P., Sommer, B., Staufenbiel, M., Wiederhold, K. H., et al. (2003). Neuropeptide alterations in the hippocampal formation and cortex of transgenic mice overexpressing beta-amyloid precursor protein (APP) with the Swedish double mutation (APP23). Neurobiology of Diseases, 14, 579–594.

    Article  CAS  Google Scholar 

  • Earl, J. R., Grootveld, M. C., Blake, D. R., & Morris, C. J. (1996). Effect of mu, delta and kappa opioid receptor agonists on a reactive oxygen species mediated model of skin inflammation. Skin Pharmacology, 9, 250–258.

    Article  PubMed  CAS  Google Scholar 

  • Ernst, A., Buerger, K., Hartmann, O., Dodel, R., Noelker, C., Sommer, N., et al. (2010). Midregional Proenkephalin A and N-terminal Protachykinin A are decreased in the cerebrospinal fluid of patients with dementia disorders and acute neuroinflammation. Journal of Neuroimmunology, 221, 62–67.

    Article  PubMed  CAS  Google Scholar 

  • Facchinetti, F., Storchi, A. R., Pacchetti, C., Martignoni, E., & Genazzani, A. R. (1987). Abnormal pro-opiomelanocortin processing in Alzheimer’s disease. A case report. Functional Neurology, 2, 349–353.

    PubMed  CAS  Google Scholar 

  • Feuerstein, T. J., Gleichauf, O., Peckys, D., Landwehrmeyer, G. B., Scheremet, R., & Jackisch, R. (1996). Opioid receptor-mediated control of acetylcholine release in human neocortex tissue. Naunyn Schmiedebergs Archives of Pharmacology, 354, 586–592.

    CAS  Google Scholar 

  • Finder, V. H. (2010). Alzheimer’s disease: A general introduction and pathomechanism. Journal of Alzheimers Disease, 22(Suppl 3), 5–19.

    Google Scholar 

  • Fischetti, C., Rizzi, A., Gavioli, E. C., Marzola, G., Trapella, C., Guerrini, R., et al. (2009). Further studies on the pharmacological features of the nociceptin/orphanin FQ receptor ligand ZP120. Peptides, 30, 248–255.

    Article  PubMed  CAS  Google Scholar 

  • Florin, S., Leblond, F., Suaudeau, C., Meunier, J. C., & Costentin, J. (1999). Comparison of behavioural effects of NocII or NocIII, two related pronociceptin-derived peptides. Life Sciences, 65, 2727–2733.

    Article  PubMed  CAS  Google Scholar 

  • Florin, S., Meunier, J., & Costentin, J. (2000). Autoradiographic localization of [3H]nociceptin binding sites in the rat brain. Brain Research, 880, 11–16.

    Article  PubMed  CAS  Google Scholar 

  • Foddi, M. C., & Mennini, T. (1997). [125I][Tyr14]Orphanin binding to rat brain: Evidence for labelling the opioid-receptor-like 1 (ORL1). Neuroscience Letters, 230, 105–108.

    Article  PubMed  CAS  Google Scholar 

  • Freeman, M. P., Freeman, S. A., & McElroy, S. L. (2002). The comorbidity of bipolar and anxiety disorders: Prevalence, psychobiology, and treatment issues. Journal of Affective Disorders, 68, 1–23.

    Article  PubMed  Google Scholar 

  • Frost, J. J. (1993). Receptor imaging by PET and SPECT: Focus on the opiate receptor. Journal of Receptor Research, 13, 39–53.

    PubMed  CAS  Google Scholar 

  • Fujisawa, H., Dawson, D., Browne, S. E., MacKay, K. B., Bullock, R., & McCulloch, J. (1993). Pharmacological modification of glutamate neurotoxicity in vivo. Brain Research, 629, 73–78.

    Article  PubMed  CAS  Google Scholar 

  • Gallagher, M., & Nicolle, M. M. (1993). Animal models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry. Behavioural Brain Research, 57, 155–162.

    Article  PubMed  CAS  Google Scholar 

  • Gannon, R. L., & Terrian, D. M. (1991). U-50,488H inhibits dynorphin and glutamate release from guinea pig hippocampal mossy fiber terminals. Brain Research, 548, 242–247.

    Article  PubMed  CAS  Google Scholar 

  • Garlind, A., Cowburn, R. F., Wiehager, B., Ravid, R., Winblad, B., & Fowler, C. J. (1995). Preservation of kappa 1 opioid receptor recognition site density and regulation by G-proteins in the temporal cortex of patients with Alzheimer’s disease. Neuroscience Letters, 185, 131–134.

    Article  PubMed  CAS  Google Scholar 

  • Garreau, I., Cucumel, K., Dagouassat, N., Zhao, Q., Cupo, A., & Piot, J. M. (1997). Hemorphin peptides are released from hemoglobin by cathepsin D. Radioimmunoassay against the C-part of V-V-hemorphin-7: An alternative assay for the cathepsin D activity. Peptides, 18, 293–300.

    Article  PubMed  CAS  Google Scholar 

  • Garuba, M., Mostek, D. E., & Burke, W. J. (2009). Opioid-induced hyperalgesia in a patient with dementia. Journal of the American Geriatrics Society, 57, 748–749.

    Article  PubMed  Google Scholar 

  • Garzon, J., Hollt, V., Sanchez-Blazquez, P., & Herz, A. (1987). Neural activation of opioid mechanisms in guinea pig ileum by excitatory peptides. Journal of Pharmacology and Experimental Therapeutics, 240, 642–649.

    PubMed  CAS  Google Scholar 

  • Garzon, J., Schulz, R., & Herz, A. (1984). Application of receptor theory provides further evidence for the existence of the epsilon-opioid receptor in rat vas deferens. Neuropeptides, 5, 101–104.

    Article  PubMed  CAS  Google Scholar 

  • Gazulla, J., & Cavero-Nagore, M. (2006). Glutamate and Alzheimer’s disease. Revista de neurologia, 42, 427–432.

    PubMed  CAS  Google Scholar 

  • Giros, B., Gros, C., Llorens-Cortes, C., & Schwartz, J. C. (1987). Opioid peptides: Metabolism and receptors. Gastroenterologie Clinique et Biologique, 11, 7B–13B.

    PubMed  CAS  Google Scholar 

  • Giuliani, S., Lecci, A., Tramontana, M., & Maggi, C. A. (1996). Role of kappa opioid receptors in modulating cholinergic twitches in the circular muscle of guinea-pig colon. British Journal of Pharmacology, 119, 985–989.

    PubMed  CAS  Google Scholar 

  • Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140, 918–934.

    Article  PubMed  CAS  Google Scholar 

  • Godridge, H., Reynolds, G. P., Czudek, C., Calcutt, N. A., & Benton, M. (1987). Alzheimer-like neurotransmitter deficits in adult Down’s syndrome brain tissue. Journal of Neurology, Neurosurgery and Psychiatry, 50, 775–778.

    Article  CAS  Google Scholar 

  • Goeldner, C., Reiss, D., Wichmann, J., Meziane, H., Kieffer, B. L., & Ouagazzal, A. M. (2008). Nociceptin receptor impairs recognition memory via interaction with NMDA receptor-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in the hippocampus. Journal of Neuroscience, 28, 2190–2198.

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez Nunez, V., Gonzalez Sarmiento, R., & Rodriguez, R. E. (2003). Characterization of zebrafish proenkephalin reveals novel opioid sequences. Brain Research. Molecular Brain Research, 114, 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Grassel, S., Opolka, A., Anders, S., Straub, R. H., Grifka, J., Luger, T. A., et al. (2009). The melanocortin system in articular chondrocytes: Melanocortin receptors, pro-opiomelanocortin, precursor proteases, and a regulatory effect of alpha-melanocyte-stimulating hormone on proinflammatory cytokines and extracellular matrix components. Arthritis and Rheumatism, 60, 3017–3027.

    Article  PubMed  CAS  Google Scholar 

  • Greenamyre, J. T., Maragos, W. F., Albin, R. L., Penney, J. B., & Young, A. B. (1988). Glutamate transmission and toxicity in Alzheimer’s disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 12, 421–430.

    Article  PubMed  CAS  Google Scholar 

  • Gulya, K., Gehlert, D. R., Wamsley, J. K., Mosberg, H., Hruby, V. J., & Yamamura, H. I. (1986). Light microscopic autoradiographic localization of delta opioid receptors in the rat brain using a highly selective bis-penicillamine cyclic enkephalin analog. Journal of Pharmacology and Experimental Therapeutics, 238, 720–726.

    PubMed  CAS  Google Scholar 

  • Hadjiconstantinou, M., & Neff, N. H. (2011). Nicotine and endogenous opioids: Neurochemical and pharmacological evidence. Neuropharmacology, 60, 1209–1220.

    Article  PubMed  CAS  Google Scholar 

  • Haroutunian, V., Santucci, A. C., & Davis, K. L. (1990). Implications of multiple transmitter system lesions for cholinomimetic therapy in Alzheimer’s disease. Progress in Brain Research, 84, 333–346.

    Article  PubMed  CAS  Google Scholar 

  • Heilig, M., & Egli, M. (2006). Pharmacological treatment of alcohol dependence: Target symptoms and target mechanisms. Pharmacology & Therapeutics, 111, 855–876.

    Article  CAS  Google Scholar 

  • Heiss, W. D., & Herholz, K. (2006). Brain receptor imaging. Journal of Nuclear Medicine, 47, 302–312.

    PubMed  CAS  Google Scholar 

  • Heneka, M. T., Nadrigny, F., Regen, T., Martinez-Hernandez, A., Dumitrescu-Ozimek, L., Terwel, D., et al. (2010). Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proceedings of the National Academy of Sciences of the U S A, 107, 6058–6063.

    Article  CAS  Google Scholar 

  • Hiller, J. M., Itzhak, Y., & Simon, E. J. (1986). Limbic regions of the brain of Alzheimer’s disease patients show selective changes in mu, delta and kappa opioid receptor binding. NIDA Research Monograph, 75, 559–562.

    PubMed  CAS  Google Scholar 

  • Hiller, J. M., Itzhak, Y., & Simon, E. J. (1987). Selective changes in mu, delta and kappa opioid receptor binding in certain limbic regions of the brain in Alzheimer’s disease patients. Brain Research, 406, 17–23.

    Article  PubMed  CAS  Google Scholar 

  • Hiramatsu, M., Inoue, K., & Kameyama, T. (2000). Dynorphin A-(1-13) and (2-13) improve beta-amyloid peptide-induced amnesia in mice. NeuroReport, 11, 431–435.

    Article  PubMed  CAS  Google Scholar 

  • Hirota, K., Okawa, H., Appadu, B. L., Grandy, D. K., Devi, L. A., & Lambert, D. G. (1999). Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology, 90, 174–182.

    Article  PubMed  CAS  Google Scholar 

  • Hjorth, S. A., Thirstrup, K., & Schwartz, T. W. (1996). Radioligand-dependent discrepancy in agonist affinities enhanced by mutations in the kappa-opioid receptor. Molecular Pharmacology, 50, 977–984.

    PubMed  CAS  Google Scholar 

  • Holden, J. E., Jeong, Y., & Forrest, J. M. (2005). The endogenous opioid system and clinical pain management. AACN Clinical Issues, 16, 291–301.

    Article  PubMed  Google Scholar 

  • Homberg, J. R., Mul, J. D., de Wit, E., & Cuppen, E. (2009). Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in mu, delta and kappa opioid receptors. Neuroscience, 163, 308–315.

    Article  PubMed  CAS  Google Scholar 

  • Hook, V. Y. (2006). Protease pathways in peptide neurotransmission and neurodegenerative diseases. Cellular and Molecular Neurobiology, 26, 449–469.

    Article  PubMed  CAS  Google Scholar 

  • Howe, E. G. (2006). Do we undervalue feelings in patients who are cognitively impaired? Journal of Clinical Ethics, 17, 291–301.

    PubMed  Google Scholar 

  • Howell, O., Atack, J. R., Dewar, D., McKernan, R. M., & Sur, C. (2000). Density and pharmacology of alpha5 subunit-containing GABA(A) receptors are preserved in hippocampus of Alzheimer’s disease patients. Neuroscience, 98, 669–675.

    Article  PubMed  CAS  Google Scholar 

  • Hruby, V. J., & Agnes, R. S. (1999). Conformation-activity relationships of opioid peptides with selective activities at opioid receptors. Biopolymers, 51, 391–410.

    Article  PubMed  CAS  Google Scholar 

  • Hu, S., Sheng, W. S., & Rock, R. B. (2011). Immunomodulatory properties of kappa opioids and synthetic cannabinoids in HIV-1 neuropathogenesis. Journal of Neuroimmune Pharmacology, 6, 528–539.

    Article  PubMed  Google Scholar 

  • Hugon, J., Esclaire, F., Terro, F., & Yardin, C. (2000). Apoptosis and Alzheimer disease. Contribution of cellular and transgenic models. Revue neurologique, 156, 123–125.

    PubMed  CAS  Google Scholar 

  • Hui, K. S. (2007). Brain-specific aminopeptidase: From enkephalinase to protector against neurodegeneration. Neurochemical Research, 32, 2062–2071.

    Article  PubMed  CAS  Google Scholar 

  • Hyman, B. T., Eslinger, P. J., & Damasio, A. R. (1985). Effect of naltrexone on senile dementia of the Alzheimer type. Journal of Neurology, Neurosurgery and Psychiatry, 48, 1169–1171.

    Article  CAS  Google Scholar 

  • Hynd, M. R., Scott, H. L., & Dodd, P. R. (2004). Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochemistry International, 45, 583–595.

    Article  PubMed  CAS  Google Scholar 

  • Hytrek, S. D., Smith, J. P., McGarrity, T. J., McLaughlin, P. J., Lang, C. M., & Zagon, I. S. (1996). Identification and characterization of zeta-opioid receptor in human colon cancer. American Journal of Physiology, 271, R115–R121.

    PubMed  CAS  Google Scholar 

  • Ianzer, D., Konno, K., Xavier, C. H., Stocklin, R., Santos, R. A., de Camargo, A. C., et al. (2006). Hemorphin and hemorphin-like peptides isolated from dog pancreas and sheep brain are able to potentiate bradykinin activity in vivo. Peptides, 27, 2957–2966.

    Article  PubMed  CAS  Google Scholar 

  • Ibba, M., Kitayama, M., McDonald, J., Calo, G., Guerrini, R., Farkas, J., et al. (2008). Binding of the novel radioligand [(3)H]UFP-101 to recombinant human and native rat nociceptin/orphanin FQ receptors. Naunyn-Schmiedeberg’s Archives of Pharmacology, 378, 553–561.

    Article  PubMed  CAS  Google Scholar 

  • Ionov, I. D., & Pushinskaya, I. I. (2010). Amyloid-beta production in aged guinea pigs: Atropine-induced enhancement is reversed by naloxone. Neuroscience Letters, 480, 83–86.

    Article  PubMed  CAS  Google Scholar 

  • Israel, Y., Kandov, Y., Khaimova, E., Kest, A., Lewis, S. R., Pasternak, G. W., et al. (2005). NPY-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. Peptides, 26, 1167–1175.

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto, E. T. (1981). Locomotor activity and antinociception after putative mu, kappa and sigma opioid receptor agonists in the rat: Influence of dopaminergic agonists and antagonists. Journal of Pharmacology and Experimental Therapeutics, 217, 451–460.

    PubMed  CAS  Google Scholar 

  • Jackson, H. C., Ripley, T. L., & Nutt, D. J. (1989). Exploring delta-receptor function using the selective opioid antagonist naltrindole. Neuropharmacology, 28, 1427–1430.

    Article  PubMed  CAS  Google Scholar 

  • James, R. C., Wessinger, W. D., Roberts, S. M., Millner, G. C., & Paule, M. G. (1988). Centrally mediated opioid induced depression of hepatic glutathione: Effects of intracerebroventricular administration of mu, kappa, sigma and delta agonists. Toxicology, 51, 267–279.

    Article  PubMed  CAS  Google Scholar 

  • Jansen, K. L., Faull, R. L., Dragunow, M., & Synek, B. L. (1990). Alzheimer’s disease: changes in hippocampal N-methyl-d-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study. Neuroscience, 39, 613–627.

    Article  PubMed  CAS  Google Scholar 

  • Jeftinija, S. (1988). Enkephalins modulate excitatory synaptic transmission in the superficial dorsal horn by acting at mu-opioid receptor sites. Brain Research, 460, 260–268.

    Article  PubMed  CAS  Google Scholar 

  • Jenab, S., Kest, B., Franklin, S. O., & Inturrisi, C. E. (1995). Quantitative distribution of the delta opioid receptor mRNA in the mouse and rat CNS. Life Sciences, 56, 2343–2355.

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Corral, C., Moran-Sanchez, J. C., & Alonso-Navarro, H. (2006). Neuropeptides in Alzheimer’s disease. Revista de neurologia, 42, 354–359.

    PubMed  CAS  Google Scholar 

  • Jinsmaa, Y., & Yoshikawa, M. (2002). Release of hemorphin-5 from human hemoglobin by pancreatic elastase. Bioscience, Biotechnology, and Biochemistry, 66, 1130–1132.

    Article  PubMed  CAS  Google Scholar 

  • Jones, E. G. (1986). Neurotransmitters in the cerebral cortex. Journal of Neurosurgery, 65, 135–153.

    Article  PubMed  CAS  Google Scholar 

  • Kalman, J., Bjelik, A., Hugyecz, M., Timar, J., Gyarmati, Z., Zana, M., et al. (2007). 3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain. International Journal of Neuropsychopharmacology, 10, 183–190.

    Article  PubMed  CAS  Google Scholar 

  • Kalyuzhny, A. E., Dooyema, J., & Wessendorf, M. W. (2000). Opioid- and GABA(A)-receptors are co-expressed by neurons in rat brain. NeuroReport, 11, 2625–2628.

    Article  PubMed  CAS  Google Scholar 

  • Kapusta, D. R., Burmeister, M. A., Calo, G., Guerrini, R., Gottlieb, H. B., & Kenigs, V. A. (2005). Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function. Journal of Pharmacology and Experimental Therapeutics, 314, 643–651.

    Article  PubMed  CAS  Google Scholar 

  • Kapusta, D. R., & Obih, J. C. (1993). Central kappa opioid receptor-evoked changes in renal function in conscious rats: Participation of renal nerves. Journal of Pharmacology and Experimental Therapeutics, 267, 197–204.

    PubMed  CAS  Google Scholar 

  • Kasakov, L., Nashar, M., Naydenova, E., Vezenkov, L., & Vlaskovska, M. (2010). In vitro studies of the activity of newly synthesized nociceptin/orphanin FQ receptor ligand analogues. Protein and Peptide Letters, 17, 616–620.

    Article  PubMed  CAS  Google Scholar 

  • Kawano, S., Ambo, A., & Sasaki, Y. (2006). Synthesis and receptor binding properties of chimeric peptides containing a mu-opioid receptor ligand and nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-amide. Bioorganic & Medicinal Chemistry Letters, 16, 4839–4841.

    Article  CAS  Google Scholar 

  • Kirvell, S. L., Esiri, M., & Francis, P. T. (2006). Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer’s disease. Journal of Neurochemistry, 98, 939–950.

    Article  PubMed  CAS  Google Scholar 

  • Kitayama, M., McDonald, J., Barnes, T. A., Calo, G., Guerrini, R., Rowbotham, D. J., et al. (2007). In vitro pharmacological characterisation of a novel cyclic nociceptin/orphanin FQ analogue c[Cys(7,10)]N/OFQ(1-13)NH (2. Naunyn-Schmiedeberg’s Archives of Pharmacology, 375, 369–376.

    Article  PubMed  CAS  Google Scholar 

  • Kitchen, I., Leslie, F. M., Kelly, M., Barnes, R., Crook, T. J., Hill, R. G., et al. (1995). Development of delta-opioid receptor subtypes and the regulatory role of weaning: Radioligand binding, autoradiography and in situ hybridization studies. Journal of Pharmacology and Experimental Therapeutics, 275, 1597–1607.

    PubMed  CAS  Google Scholar 

  • Klunk, W. E., Debnath, M. L., McClure, R. J., & Pettegrew, J. W. (1995). Inactivity of phosphoethanolamine, an endogenous GABA analog decreased in Alzheimer’s disease, at GABA binding sites. Life Sciences, 56, 2377–2383.

    Article  PubMed  CAS  Google Scholar 

  • Knapp, R. J., & Yamamura, H. I. (1990). [3H][D-Pen2, D-Pen5]enkephalin binding to delta opioid receptors on intact neuroblastoma-glioma (NG 108-15) hybrid cells. Life Sciences, 46, 1457–1463.

    Article  PubMed  CAS  Google Scholar 

  • Kong, H., Raynor, K., Yano, H., Takeda, J., Bell, G. I., & Reisine, T. (1994). Agonists and antagonists bind to different domains of the cloned kappa opioid receptor. Proceedings of the National Academy of Sciences of the U S A, 91, 8042–8046.

    Article  CAS  Google Scholar 

  • Kosterlitz, H. W. (1980). Opioid peptides and their receptors. Progress in Biochemical Pharmacology, 16, 3–10.

    PubMed  CAS  Google Scholar 

  • Kurt, M. A., Davies, D. C., & Kidd, M. (1997). Paired helical filament morphology varies with intracellular location in Alzheimer’s disease brain. Neuroscience Letters, 239, 41–44.

    Article  PubMed  CAS  Google Scholar 

  • Kuzmin, A., Madjid, N., Terenius, L., Ogren, S. O., & Bakalkin, G. (2006). Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology, 31, 1928–1937.

    Article  PubMed  CAS  Google Scholar 

  • Law, A., Gauthier, S., & Quirion, R. (2001). Say NO to Alzheimer’s disease: The putative links between nitric oxide and dementia of the Alzheimer’s type. Brain Research. Brain Research Reviews, 35, 73–96.

    Article  PubMed  CAS  Google Scholar 

  • Lemaire, S., Day, R., Dumont, M., Chouinard, L., & Calvert, R. (1984). Dynorphin and enkephalins in adrenal paraneurones. Opiates in the adrenal medulla. Canadian Journal of Physiology and Pharmacology, 62, 484–492.

    Article  PubMed  CAS  Google Scholar 

  • Lengauer, E. (2007). Drug dependent adolescents have Alzheimer disease-like brains. Kinderkrankenschwester, 26, 37.

    Google Scholar 

  • Leskela, T. T., Markkanen, P. M., Alahuhta, I. A., Tuusa, J. T., & Petaja-Repo, U. E. (2009). Phe27Cys polymorphism alters the maturation and subcellular localization of the human delta opioid receptor. Traffic, 10, 116–129.

    Article  PubMed  CAS  Google Scholar 

  • Lester, P. A., & Traynor, J. R. (2006). Comparison of the in vitro efficacy of mu, delta, kappa and ORL1 receptor agonists and non-selective opioid agonists in dog brain membranes. Brain Research, 1073–1074, 290–296.

    Article  PubMed  CAS  Google Scholar 

  • Leung, K. (2004a). [6-O-methyl-11C]Diprenorphine.

  • Leung, K. (2004b). (20R)-4,5-alpha-Epoxy-17-methyl-3-hydroxy-6-[11C]methoxy-alpha,17-dimethyl -alpha-(2-phenylethyl)-6,14-ethenomorphinan-7-methanol.

  • Leung, K. (2004c). DY-675-g7-Poly(lactic-co-glycolic acid) nanoparticles.

  • Lew, G. M. (1997). Changes in microtubular tau protein after morphine in a cultured human neuroblastoma cell line. General Pharmacology, 29, 869–872.

    PubMed  CAS  Google Scholar 

  • Li, J. Q., Huang, L. Y., Chen, X. J., Weng, Z. J., & Zhang, C. N. (2008). Synthesis and central none-opioid analgesic activity of SIPI5047. Yao Xue Xue Bao, 43, 611–618.

    PubMed  Google Scholar 

  • Lin, S. L., Tsai, R. Y., Tai, Y. H., Cherng, C. H., Wu, C. T., Yeh, C. C., et al. (2010). Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords. Behavioural Brain Research, 207, 30–36.

    Article  PubMed  CAS  Google Scholar 

  • Liu, C. H., Cherng, C. H., Lin, S. L., Yeh, C. C., Wu, C. T., Tai, Y. H., et al. (2011). N-methyl-d-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats. Pharmacology, Biochemistry and Behavior, 99, 371–380.

    Article  CAS  Google Scholar 

  • Liu, B., & Hong, J. S. (2003). Neuroprotective effect of naloxone in inflammation-mediated dopaminergic neurodegeneration. Dissociation from the involvement of opioid receptors. Methods in Molecular Medicine, 79, 43–54.

    PubMed  CAS  Google Scholar 

  • Liu, Y., Qin, L., Wilson, B. C., An, L., Hong, J. S., & Liu, B. (2002). Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons. Journal of Pharmacology and Experimental Therapeutics, 302, 1212–1219.

    Article  PubMed  CAS  Google Scholar 

  • Loeb, C., Albano, C., & Serrati, C. (1984). Cerebrospinal fluid levels of leucine enkephalin and methionine enkephalin in patients with altered behavior. Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie, 134, 29–40.

    PubMed  CAS  Google Scholar 

  • Lolait, S. J., Clements, J. A., Markwick, A. J., Cheng, C., McNally, M., Smith, A. I., et al. (1986). Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. Journal of Clinical Investigation, 77, 1776–1779.

    Article  PubMed  CAS  Google Scholar 

  • Lomas, L. M., Barrett, A. C., Terner, J. M., Lysle, D. T., & Picker, M. J. (2007). Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats. Psychopharmacology (Berl), 191, 273–285.

    Article  CAS  Google Scholar 

  • Mackay, K. B., Dewar, D., & McCulloch, J. (1994). kappa-1 Opioid receptors of the temporal cortex are preserved in Alzheimer’s disease. Journal of Neural Transmission. Parkinson’s Disease and Dementia Section, 7, 73–79.

    Article  PubMed  CAS  Google Scholar 

  • Maggi, R., Pimpinelli, F., Martini, L., & Piva, F. (1995). Inhibition of luteinizing hormone-releasing hormone secretion by delta-opioid agonists in GT1-1 neuronal cells. Endocrinology, 136, 5177–5181.

    Article  PubMed  CAS  Google Scholar 

  • Maire, J. C., & Wurtman, R. J. (1984). Choline production from choline-containing phospholipids: A hypothetical role in Alzheimer’s disease and aging. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 8, 637–642.

    Article  PubMed  CAS  Google Scholar 

  • Makman, M. H. (1994). Morphine receptors in immunocytes and neurons. Advances in Neuroimmunology, 4, 69–82.

    Article  PubMed  CAS  Google Scholar 

  • Mancuso, M., Orsucci, D., LoGerfo, A., Calsolaro, V., & Siciliano, G. (2010). Clinical features and pathogenesis of Alzheimer’s disease: Involvement of mitochondria and mitochondrial DNA. Advances in Experimental Medicine and Biology, 685, 34–44.

    Article  PubMed  CAS  Google Scholar 

  • Mansour, A., Fox, C. A., Burke, S., Meng, F., Thompson, R. C., Akil, H., et al. (1994). Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: An in situ hybridization study. The Journal of Comparative Neurology, 350, 412–438.

    Article  PubMed  CAS  Google Scholar 

  • Mansour, A., Thompson, R. C., Akil, H., & Watson, S. J. (1993). Delta opioid receptor mRNA distribution in the brain: Comparison to delta receptor binding and proenkephalin mRNA. Journal of Chemical Neuroanatomy, 6, 351–362.

    Article  PubMed  CAS  Google Scholar 

  • Marki, A., Monory, K., Otvos, F., Toth, G., Krassnig, R., Schmidhammer, H., et al. (1999). Mu-opioid receptor specific antagonist cyprodime: Characterization by in vitro radioligand and [35S]GTPgammaS binding assays. European Journal of Pharmacology, 383, 209–214.

    Article  PubMed  CAS  Google Scholar 

  • Marti, M., Mela, F., Fantin, M., Zucchini, S., Brown, J. M., Witta, J., et al. (2005). Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. Journal of Neuroscience, 25, 9591–9601.

    Article  PubMed  CAS  Google Scholar 

  • Massino Iu, S., Tsibezov, V. V., Dmitriev, A. D., Vostrikov, V. M., & Soldatova, I. A. (1988). Monoclonal antibodies to alpha-endorphin effective in immunohistochemistry and immunoblotting. Biulleten Eksperimentalnoi Biologii I Meditsiny, 106, 578–581.

    CAS  Google Scholar 

  • Mathieu-Kia, A. M., Fan, L. Q., Kreek, M. J., Simon, E. J., & Hiller, J. M. (2001). Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients. Brain Research, 893, 121–134.

    Article  PubMed  CAS  Google Scholar 

  • Maurice, T., Su, T. P., & Privat, A. (1998). Sigma1 (sigma 1) receptor agonists and neurosteroids attenuate B25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience, 83, 413–428.

    Article  PubMed  CAS  Google Scholar 

  • May, E. L. (1992). Leads to current therapy, to opioid receptor subtypes and to sigma receptors. NIDA Research Monograph, 119, 59–70.

    PubMed  CAS  Google Scholar 

  • McDonald, J., & Lambert, D. G. (2010). Binding of GTPgamma[35S] is regulated by GDP and receptor activation. Studies with the nociceptin/orphanin FQ receptor. British Journal of Pharmacology, 159, 1286–1293.

    Article  PubMed  CAS  Google Scholar 

  • McGeer, P. L., & McGeer, E. G. (1980). Chemistry of mood and emotion. Annual Review of Psychology, 31, 273–307.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin, P. J., Sassani, J. W., Klocek, M. S., & Zagon, I. S. (2010). Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) axis with naltrexone: A review. Brain Research Bulletin, 81, 236–247.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin, P. J., & Wu, Y. (1997). Identification and characterization of the zeta-opioid receptor in developing rat heart. American Journal of Physiology, 272, R1841–R1846.

    PubMed  CAS  Google Scholar 

  • Meilandt, W. J., Yu, G. Q., Chin, J., Roberson, E. D., Palop, J. J., Wu, T., et al. (2008). Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer’s disease. Journal of Neuroscience, 28, 5007–5017.

    Article  PubMed  CAS  Google Scholar 

  • Mellor, J. R., & Randall, A. D. (2001). Synaptically released neurotransmitter fails to desensitize postsynaptic GABA(A) receptors in cerebellar cultures. Journal of Neurophysiology, 85, 1847–1857.

    PubMed  CAS  Google Scholar 

  • Melzack, R. (1999). From the gate to the neuromatrix. Pain Supplement, 6, S121–S126.

    Article  Google Scholar 

  • Mendelsohn, L. G., Kalra, V., Johnson, B. G., & Kerchner, G. A. (1985). Sigma opioid receptor: Characterization and co-identity with the phencyclidine receptor. Journal of Pharmacology and Experimental Therapeutics, 233, 597–602.

    PubMed  CAS  Google Scholar 

  • Menschik, E. D., & Finkel, L. H. (1998). Neuromodulatory control of hippocampal function: Towards a model of Alzheimer’s disease. Artificial Intelligence in Medicine, 13, 99–121.

    Article  PubMed  CAS  Google Scholar 

  • Merg, F., Filliol, D., Usynin, I., Bazov, I., Bark, N., Hurd, Y. L., et al. (2006). Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor. Journal of Neurochemistry, 97, 292–301.

    Article  PubMed  CAS  Google Scholar 

  • Meucci, E., Delay-Goyet, P., Roques, B. P., & Zajac, J. M. (1989). Binding in vivo of selective mu and delta opioid receptor agonists: Opioid receptor occupancy by endogenous enkephalins. European Journal of Pharmacology, 171, 167–178.

    Article  PubMed  CAS  Google Scholar 

  • Meunier, J. C. (1986). The opioid peptides and their receptors. Biochimie, 68, 1153–1158.

    Article  PubMed  CAS  Google Scholar 

  • Meunier, J., Ieni, J., & Maurice, T. (2006). The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. British Journal of Pharmacology, 149, 998–1012.

    Article  PubMed  CAS  Google Scholar 

  • Minami, M., Onogi, T., Toya, T., Katao, Y., Hosoi, Y., Maekawa, K., et al. (1994). Molecular cloning and in situ hybridization histochemistry for rat mu-opioid receptor. Neuroscience Research, 18, 315–322.

    Article  PubMed  CAS  Google Scholar 

  • Mizukami, K., Ikonomovic, M. D., Grayson, D. R., Sheffield, R., & Armstrong, D. M. (1998). Immunohistochemical study of GABAA receptor alpha1 subunit in the hippocampal formation of aged brains with Alzheimer-related neuropathologic changes. Brain Research, 799, 148–155.

    Article  PubMed  CAS  Google Scholar 

  • Mohr, E., Bruno, G., Foster, N., Gillespie, M., Cox, C., Hare, T. A., et al. (1986). GABA-agonist therapy for Alzheimer’s disease. Clinical Neuropharmacology, 9, 257–263.

    Article  PubMed  CAS  Google Scholar 

  • Mollereau, C., & Mouledous, L. (2000). Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides, 21, 907–917.

    Article  PubMed  CAS  Google Scholar 

  • Mollereau, C., Parmentier, M., Mailleux, P., Butour, J. L., Moisand, C., Chalon, P., et al. (1994). ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Letters, 341, 33–38.

    Article  PubMed  CAS  Google Scholar 

  • Mollereau, C., Roumy, M., & Zajac, J. M. (2005). Opioid-modulating peptides: mechanisms of action. Current Topics in Medicinal Chemistry, 5, 341–355.

    Article  PubMed  CAS  Google Scholar 

  • Mori, T., Yoshizawa, K., Nomura, M., Isotani, K., Torigoe, K., Tsukiyama, Y., et al. (2011). Sigma-1 receptor function is critical for both the discriminative stimulus and aversive effects of the kappa-opioid receptor agonist U-50488H. Addiction Biology. doi:10.1111/j.1369-1600.2010.00306.x.

  • Morin-Surun, M. P., Boudinot, E., Dubois, C., Matthes, H. W., Kieffer, B. L., Denavit-Saubie, M., et al. (2001). Respiratory function in adult mice lacking the mu-opioid receptor: Role of delta-receptors. European Journal of Neuroscience, 13, 1703–1710.

    Article  PubMed  CAS  Google Scholar 

  • Morley, J. E. (1986). Neuropeptides, behavior, and aging. Journal of the American Geriatrics Society, 34, 52–62.

    PubMed  CAS  Google Scholar 

  • Moron, J. A., Gullapalli, S., Taylor, C., Gupta, A., Gomes, I., & Devi, L. A. (2010). Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: Conditioned place preference to morphine induces CREB phosphorylation. Neuropsychopharmacology, 35, 955–966.

    Article  PubMed  CAS  Google Scholar 

  • Muhlbauer, M., Metcalf, J. C., Jr, Robertson, J. T., Fridland, G., & Desiderio, D. M. (1986). Opioid peptides in the cerebrospinal fluid of Alzheimer patients. Biomedical Chromatography, 1, 155–158.

    Article  PubMed  CAS  Google Scholar 

  • Multhaup, G. (2006). Amyloid precursor protein and BACE function as oligomers. Neurodegenerative Disease, 3, 270–274.

    Article  CAS  Google Scholar 

  • Muyllaert, D., Kremer, A., Jaworski, T., Borghgraef, P., Devijver, H., Croes, S., et al. (2008). Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology? Genes, Brain and Behavior, 7(Suppl 1), 57–66.

    CAS  Google Scholar 

  • Nagga, K., Bogdanovic, N., & Marcusson, J. (1999). GABA transporters (GAT-1) in Alzheimer’s disease. Journal of Neural Transmission, 106, 1141–1149.

    Article  PubMed  CAS  Google Scholar 

  • Nakayama, S., Taniyama, K., Matsuyama, S., Ohgushi, N., Tsunekawa, K., & Tanaka, C. (1990). Regulatory role of enteric mu and kappa opioid receptors in the release of acetylcholine and norepinephrine from guinea pig ileum. Journal of Pharmacology and Experimental Therapeutics, 254, 792–798.

    PubMed  CAS  Google Scholar 

  • Narita, M., Aoki, T., & Suzuki, T. (2001). Mechanisms of morphine-induced rewarding effect: Involvement of NMDA receptor subunits. Nippon Yakurigaku Zasshi, 117, 13–19.

    Article  PubMed  CAS  Google Scholar 

  • Narita, M., Kuzumaki, N., Miyatake, M., Sato, F., Wachi, H., Seyama, Y., et al. (2006). Role of delta-opioid receptor function in neurogenesis and neuroprotection. Journal of Neurochemistry, 97, 1494–1505.

    Article  PubMed  CAS  Google Scholar 

  • Nemeroff, C. B., & Bissette, G. (1985). Involvement of non-opioid peptides in the pathogenesis of neurological and psychiatric disorders: Evidence from CSF and post-mortem studies. Progress in Clinical and Biological Research, 192, 333–341.

    PubMed  CAS  Google Scholar 

  • Ni, Y., Zhao, X., Bao, G., Zou, L., Teng, L., Wang, Z., et al. (2006). Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nature Medicine, 12, 1390–1396.

    Article  PubMed  CAS  Google Scholar 

  • Nielsen, C. K., Simms, J. A., Bito-Onon, J. J., Li, R., Ananthan, S., & Bartlett, S. E. (2011). The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking. Addiction Biology, 17, 224–234.

    Article  PubMed  CAS  Google Scholar 

  • Nielsen, C. K., Simms, J. A., Pierson, H. B., Li, R., Saini, S. K., Ananthan, S., et al. (2008). A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats. Biological Psychiatry, 64, 974–981.

    Article  PubMed  CAS  Google Scholar 

  • Nissen, J. B., & Kragballe, K. (1997). Enkephalins modulate differentiation of normal human keratinocytes in vitro. Experimental Dermatology, 6, 222–229.

    Article  PubMed  CAS  Google Scholar 

  • Norn, S., Kruse, P. R., & Kruse, E. (2005). History of opium poppy and morphine. Dan Medicinhist Arbog, 33, 171–184.

    PubMed  Google Scholar 

  • Ong, W. Y., & Farooqui, A. A. (2005). Iron, neuroinflammation, and Alzheimer’s disease. Journal of Alzheimers Disease, 8, 183–200; discussion 209-115.

    Google Scholar 

  • Pakaski, M., & Kalman, J. (2008). Interactions between the amyloid and cholinergic mechanisms in Alzheimer’s disease. Neurochemistry International, 53, 103–111.

    Article  PubMed  CAS  Google Scholar 

  • Parihar, M. S., & Hemnani, T. (2004). Alzheimer’s disease pathogenesis and therapeutic interventions. Journal of Clinical Neuroscience, 11, 456–467.

    Article  PubMed  CAS  Google Scholar 

  • Paterlini, M. G. (2005). The function of the extracellular regions in opioid receptor binding: Insights from computational biology. Current Topics in Medicinal Chemistry, 5, 357–367.

    Article  PubMed  CAS  Google Scholar 

  • Paul, D., Gauthier, C. A., Minor, L. D., & Gonzales, G. R. (1997). The effects of postmortem delay on mu, delta and kappa opioid receptor subtypes in rat brain and guinea pig cerebellum evaluated by radioligand receptor binding. Life Sciences, 61, 1993–1998.

    Article  PubMed  CAS  Google Scholar 

  • Perry, E. (1988). Acetylcholine and Alzheimer’s disease. British Journal of Psychiatry, 152, 737–740.

    Article  PubMed  CAS  Google Scholar 

  • Perry, E. K., Tomlinson, B. E., Blessed, G., Perry, R. H., Cross, A. J., & Crow, T. J. (1981). Neuropathological and biochemical observations on the noradrenergic system in Alzheimer’s disease. Journal of the Neurological Sciences, 51, 279–287.

    Article  PubMed  CAS  Google Scholar 

  • Petaja-Repo, U. E., Hogue, M., Laperriere, A., Walker, P., & Bouvier, M. (2000). Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor. Journal of Biological Chemistry, 275, 13727–13736.

    Article  PubMed  CAS  Google Scholar 

  • Petty, F., Davis, L. L., Kabel, D., & Kramer, G. L. (1996). Serotonin dysfunction disorders: A behavioral neurochemistry perspective. Journal of Clinical Psychiatry, 57(Suppl 8), 11–16.

    PubMed  Google Scholar 

  • Pike, V. W., Rash, K. S., Chen, Z., Pedregal, C., Statnick, M. A., Kimura, Y., et al. (2011). Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography. Journal of Medicinal Chemistry, 54, 2687–2700.

    Article  PubMed  CAS  Google Scholar 

  • Pitkanen, A., Jolkkonen, J., & Riekkinen, P. (1987). Beta-endorphin, somatostatin, and prolactin levels in cerebrospinal fluid of epileptic patients after generalised convulsion. Journal of Neurology, Neurosurgery and Psychiatry, 50, 1294–1297.

    Article  CAS  Google Scholar 

  • Poisnel, G., Oueslati, F., Dhilly, M., Delamare, J., Perrio, C., Debruyne, D., et al. (2008). [11C]-MeJDTic: A novel radioligand for kappa-opioid receptor positron emission tomography imaging. Nuclear Medicine and Biology, 35, 561–569.

    Article  PubMed  CAS  Google Scholar 

  • Poljak, A., McLean, C. A., Sachdev, P., Brodaty, H., & Smythe, G. A. (2004). Quantification of hemorphins in Alzheimer’s disease brains. Journal of Neuroscience Research, 75, 704–714.

    Article  PubMed  CAS  Google Scholar 

  • Porthe, G., Frances, B., Verrier, B., Cros, J., & Meunier, J. C. (1988). The kappa-opioid receptor from human placenta: Hydrodynamic characteristics and evidence for its association with a G protein. Life Sciences, 43, 559–567.

    Article  PubMed  CAS  Google Scholar 

  • Price, D. L., Kitt, C. A., Struble, R. G., Whitehouse, P. J., Cork, L. C., & Walker, L. C. (1985). Neurobiological studies of transmitter systems in aging and in Alzheimer-type dementia. Annals of the New York Academy of Sciences, 457, 35–51.

    Article  PubMed  CAS  Google Scholar 

  • Price, D. L., Sisodia, S. S., & Gandy, S. E. (1995). Amyloid beta amyloidosis in Alzheimer’s disease. Current Opinion in Neurology, 8, 268–274.

    Article  PubMed  CAS  Google Scholar 

  • Querfurth, H. W., & LaFerla, F. M. (2010). Alzheimer’s disease. New England Journal of Medicine, 362, 329–344.

    Article  PubMed  CAS  Google Scholar 

  • Quirarte, G. L., Galvez, R., Roozendaal, B., & McGaugh, J. L. (1998). Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs. Brain Research, 808, 134–140.

    Article  PubMed  CAS  Google Scholar 

  • Rainero, I., May, C., Kaye, J. A., Friedland, R. P., & Rapoport, S. I. (1988). CSF alpha-MSH in dementia of the Alzheimer type. Neurology, 38, 1281–1284.

    PubMed  CAS  Google Scholar 

  • Ranganathan, P., Chen, H., Adelman, M. K., & Schluter, S. F. (2009). Autoantibodies to the delta-opioid receptor function as opioid agonists and display immunomodulatory activity. Journal of Neuroimmunology, 217, 65–73.

    Article  PubMed  CAS  Google Scholar 

  • Raut, A., Iglewski, M., & Ratka, A. (2006). Differential effects of impaired mitochondrial energy production on the function of mu and delta opioid receptors in neuronal SK-N-SH cells. Neuroscience Letters, 404, 242–246.

    Article  PubMed  CAS  Google Scholar 

  • Raymon, H. K., & Leslie, F. M. (1994). Opioid effects on [3H]norepinephrine release from dissociated embryonic locus coeruleus cell cultures. Journal of Neurochemistry, 62, 1015–1024.

    Article  PubMed  CAS  Google Scholar 

  • Rinne, J. O., Lonnberg, P., Marjamaki, P., Molsa, P., Sako, E., & Paljarvi, L. (1993). Brain methionine- and leucine-enkephalin receptors in patients with dementia. Neuroscience Letters, 161, 77–80.

    Article  PubMed  CAS  Google Scholar 

  • Rissman, R. A., De Blas, A. L., & Armstrong, D. M. (2007). GABA(A) receptors in aging and Alzheimer’s disease. Journal of Neurochemistry, 103, 1285–1292.

    Article  PubMed  CAS  Google Scholar 

  • Rizzi, A., Rizzi, D., Marzola, G., Regoli, D., Larsen, B. D., Petersen, J. S., et al. (2002). Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice. British Journal of Pharmacology, 137, 369–374.

    Article  PubMed  CAS  Google Scholar 

  • Roane, D. S., Iadarola, M. J., & Porter, J. R. (1988). Decreased [3H]-naloxone binding and elevated dynorphin-A(1-8) content in Zucker rat brain. Physiology & Behavior, 43, 371–374.

    Article  CAS  Google Scholar 

  • Roberts, E., & Sherman, M. A. (1993). GABA–the quintessential neurotransmitter: Electroneutrality, fidelity, specificity, and a model for the ligand binding site of GABAA receptors. Neurochemical Research, 18, 365–376.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, E., Shoureshi, P., Kozak, K., Szynskie, L., Baron, A., Lecaude, S., et al. (2007). Tracking the evolution of the proenkephalin gene in tetrapods. General and Comparative Endocrinology, 153, 189–197.

    Article  PubMed  CAS  Google Scholar 

  • Roggo, S. (2002). Inhibition of BACE, a promising approach to Alzheimer’s disease therapy. Current Topics in Medicinal Chemistry, 2, 359–370.

    Article  PubMed  CAS  Google Scholar 

  • Roth, K. A. (2001). Caspases, apoptosis, and Alzheimer disease: Causation, correlation, and confusion. Journal of Neuropathology and Experimental Neurology, 60, 829–838.

    PubMed  CAS  Google Scholar 

  • Roy, S., Charboneau, R. G., Barke, R. A., & Loh, H. H. (2001). Role of mu-opioid receptor in immune function. Advances in Experimental Medicine and Biology, 493, 117–126.

    Article  PubMed  CAS  Google Scholar 

  • Rubaj, A., Zgodzinski, W., Gustaw, K., & Sieklucka-Dziuba, M. (2002). Nociceptin, OP4 receptor ligand in different models of experimental epilepsy. Peptides, 23, 497–505.

    Article  PubMed  CAS  Google Scholar 

  • Sandyk, R. (1987). Opioid neuronal denervation in Gilles de la Tourette syndrome. International Journal of Neuroscience, 35, 95–98.

    Article  PubMed  CAS  Google Scholar 

  • Sandyk, R. (1989). Abnormal opiate receptor functions in Tourette’s syndrome. International Journal of Neuroscience, 44, 209–214.

    Article  PubMed  CAS  Google Scholar 

  • Sarajarvi, T., Tuusa, J. T., Haapasalo, A., Lackman, J. J., Sormunen, R., Helisalmi, S., et al. (2011). Cysteine 27 variant of the {delta}-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking. Molecular and Cellular Biology, 31, 2326–2340.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, R., Bach, M., Dal-Bianco, P., Holzer, P., Pluta-Fuerst, A., Assem-Hilger, E., et al. (2010). Dementia and pain. Neuropsychiatrie, 24, 1–13.

    PubMed  CAS  Google Scholar 

  • Schmitt, H. P. (2005). Pouring oil into the fire? On the conundrum of the beneficial effects of NMDA receptor antagonists in Alzheimer disease. Psychopharmacology (Berl), 179, 151–153.

    Article  CAS  Google Scholar 

  • Schramm, C. L., & Honda, C. N. (2010). Co-administration of delta- and mu-opioid receptor agonists promotes peripheral opioid receptor function. Pain, 151, 763–770.

    Article  PubMed  CAS  Google Scholar 

  • Schunk, E., Aigner, C., Stefanova, N., Wenning, G., Herzog, H., & Schwarzer, C. (2010). Kappa opioid receptor activation blocks progressive neurodegeneration after kainic acid injection. Hippocampus. doi:10.1002/hipo.20813.

  • Scott, H. A., Gebhardt, F. M., Mitrovic, A. D., Vandenberg, R. J., & Dodd, P. R. (2011). Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiology of Aging, 32(3), 553.e1–553.e11.

    Article  CAS  Google Scholar 

  • Seidl, R., Cairns, N., Singewald, N., Kaehler, S. T., & Lubec, G. (2001). Differences between GABA levels in Alzheimer’s disease and Down syndrome with Alzheimer-like neuropathology. Naunyn-Schmiedeberg’s Archives of Pharmacology, 363, 139–145.

    Article  PubMed  CAS  Google Scholar 

  • Shen, C. H., Tsai, R. Y., Shih, M. S., Lin, S. L., Tai, Y. H., Chien, C. C., et al. (2011). Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesthesia and Analgesia, 112, 454–459.

    Article  PubMed  CAS  Google Scholar 

  • Sherif, F., Gottfries, C. G., Alafuzoff, I., & Oreland, L. (1992). Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer’s disease. Journal of Neural Transmission. Parkinson’s Disease and Dementia Section, 4, 227–240.

    Article  PubMed  CAS  Google Scholar 

  • Shiah, I. S., & Yatham, L. N. (1998). GABA function in mood disorders: An update and critical review. Life Sciences, 63, 1289–1303.

    Article  PubMed  CAS  Google Scholar 

  • Simmons, M. L., Wagner, J. J., Caudle, R. M., & Chavkin, C. (1992). Endogenous opioid regulation of norepinephrine release in guinea pig hippocampus. Neuroscience Letters, 141, 84–88.

    Article  PubMed  CAS  Google Scholar 

  • Simonds, W. F. (1988). The molecular basis of opioid receptor function. Endocrine Reviews, 9, 200–212.

    Article  PubMed  CAS  Google Scholar 

  • Simpson, M. D., Cross, A. J., Slater, P., & Deakin, J. F. (1988). Loss of cortical GABA uptake sites in Alzheimer’s disease. Journal of Neural Transmission, 71, 219–226.

    Article  PubMed  CAS  Google Scholar 

  • Singh, I. N., Goody, R. J., Goebel, S. M., Martin, K. M., Knapp, P. E., Marinova, Z., et al. (2003). Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation. Neuroscience, 122, 1013–1023.

    Article  PubMed  CAS  Google Scholar 

  • Sisodia, S. S., & Price, D. L. (1995). Role of the beta-amyloid protein in Alzheimer’s disease. FASEB Journal, 9, 366–370.

    PubMed  CAS  Google Scholar 

  • Snyder, S. H., & Childers, S. R. (1979). Opiate receptors and opioid peptides. Annual Review of Neuroscience, 2, 35–64.

    Article  PubMed  CAS  Google Scholar 

  • Su, T. P., Shukla, K., & Gund, T. (1990). Steroid binding at sigma receptors: CNS and immunological implications. Ciba Foundation Symposium, 153, 107–113; discussion 113-106.

    Google Scholar 

  • Subiran, N., Casis, L., & Irazusta, J. (2011). Regulation of male fertility by the opioid system. Molecular Medicine, 17, 846–853.

    Article  PubMed  CAS  Google Scholar 

  • Sugino, T., Shimazoe, T., Ikeda, M., & Watanabe, S. (2006). Role of nociceptin and opioid receptor like 1 on entrainment function in the rat suprachiasmatic nucleus. Neuroscience, 137, 537–544.

    Article  PubMed  CAS  Google Scholar 

  • Sulkava, R., Erkinjuntti, T., & Laatikainen, T. (1985). CSF beta-endorphin and beta-lipotropin in Alzheimer’s disease and multi-infarct dementia. Neurology, 35, 1057–1058.

    PubMed  CAS  Google Scholar 

  • Summers, W. K. (2004). Alzheimer’s disease, oxidative injury, and cytokines. Journal of Alzheimers Disease, 6, 651–657; discussion 673-681.

    Google Scholar 

  • Szegedi, V., Juhasz, G., Rozsa, E., Juhasz-Vedres, G., Datki, Z., Fulop, L., et al. (2006). Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo. FASEB Journal, 20, 1191–1193.

    Article  PubMed  CAS  Google Scholar 

  • Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Sugimoto, H., & Akaike, A. (2006). Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology, 51, 474–486.

    Article  PubMed  CAS  Google Scholar 

  • Taniguchi, H., Yomota, E., Nogi, K., Onoda, Y., & Ikezawa, K. (1998). The effect of nociceptin, an endogenous ligand for the ORL1 receptor, on rat colonic contraction and transit. European Journal of Pharmacology, 353, 265–271.

    Article  PubMed  CAS  Google Scholar 

  • Tan-No, K., Esashi, A., Nakagawasai, O., Niijima, F., Tadano, T., Sakurada, C., et al. (2002). Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Research, 952, 7–14.

    Article  PubMed  CAS  Google Scholar 

  • Tanovic, A., & Alfaro, V. (2006). Glutamate-related excitotoxicity neuroprotection with memantine, an uncompetitive antagonist of NMDA-glutamate receptor, in Alzheimer’s disease and vascular dementia. Revista de neurologia, 42, 607–616.

    PubMed  CAS  Google Scholar 

  • Tao, R., & Auerbach, S. B. (2002). Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. Journal of Pharmacology and Experimental Therapeutics, 303, 549–556.

    Article  PubMed  CAS  Google Scholar 

  • Tariot, P. N., Sunderland, T., Murphy, D. L., Cohen, M. R., Welkowitz, J. A., Weingartner, H., et al. (1986). Design and interpretation of opiate antagonist trials in dementia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 10, 611–626.

    Article  PubMed  CAS  Google Scholar 

  • Tariot, P. N., Upadhyaya, A., Sunderland, T., Cox, C., Cohen, R. M., Murphy, D. L., et al. (1999). Physiologic and neuroendocrine responses to intravenous naloxone in subjects with Alzheimer’s disease and age-matched controls. Biological Psychiatry, 46, 412–419.

    Article  PubMed  CAS  Google Scholar 

  • Taverna, F. A., Georgiou, J., McDonald, R. J., Hong, N. S., Kraev, A., Salter, M. W., et al. (2005). Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation. Journal of Physiology, 565, 579–591.

    Article  PubMed  CAS  Google Scholar 

  • Teng, L., Zhao, J., Wang, F., Ma, L., & Pei, G. (2010). A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD pathogenesis. Cell Research, 20, 138–153.

    Article  PubMed  CAS  Google Scholar 

  • Terman, G. W., Drake, C. T., Simmons, M. L., Milner, T. A., & Chavkin, C. (2000). Opioid modulation of recurrent excitation in the hippocampal dentate gyrus. Journal of Neuroscience, 20, 4379–4388.

    PubMed  CAS  Google Scholar 

  • Tian, M., Broxmeyer, H. E., Fan, Y., Lai, Z., Zhang, S., Aronica, S., et al. (1997). Altered hematopoiesis, behavior, and sexual function in mu opioid receptor-deficient mice. Journal of Experimental Medicine, 185, 1517–1522.

    Article  PubMed  CAS  Google Scholar 

  • Tillakaratne, N. J., Medina-Kauwe, L., & Gibson, K. M. (1995). gamma-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comparative Biochemistry and Physiology Part A, Physiology, 112, 247–263.

    Article  PubMed  CAS  Google Scholar 

  • Toll, L., Khroyan, T. V., Polgar, W. E., Jiang, F., Olsen, C., & Zaveri, N. T. (2009). Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociceptin receptor/mu-opioid receptor ligands: Implications for therapeutic applications. Journal of Pharmacology and Experimental Therapeutics, 331, 954–964.

    Article  PubMed  CAS  Google Scholar 

  • Tongjaroenbungam, W., Jongkamonwiwat, N., Cunningham, J., Phansuwan-Pujito, P., Dodson, H. C., Forge, A., et al. (2004). Opioid modulation of GABA release in the rat inferior colliculus. BMC Neuroscience, 5, 31.

    Article  PubMed  CAS  Google Scholar 

  • Town, T., Schinka, J., Tan, J., & Mullan, M. (2000). The opioid receptor system and alcoholism: A genetic perspective. European Journal of Pharmacology, 410, 243–248.

    Article  PubMed  CAS  Google Scholar 

  • Tsai, R. Y., Jang, F. L., Tai, Y. H., Lin, S. L., Shen, C. H., & Wong, C. S. (2008). Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats. Neuropsychopharmacology, 33, 2772–2782.

    Article  PubMed  CAS  Google Scholar 

  • Tsai, R. Y., Tai, Y. H., Tzeng, J. I., Cherng, C. H., Yeh, C. C., & Wong, C. S. (2009). Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats by reversing the coupling of mu-opioid receptors from Gs-protein to coupling to Gi-protein. Neuroscience, 164, 435–443.

    Article  PubMed  CAS  Google Scholar 

  • Tseng, L. F. (2001). Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced analgesia. Trends in Pharmacological Sciences, 22, 623–630.

    Article  PubMed  CAS  Google Scholar 

  • Tunnicliff, G., Welborn, K. L., & Ngo, T. T. (1985). Identification of potential GABA-mimetics by their actions on brain GABA recognition sites. General Pharmacology, 16, 25–29.

    PubMed  CAS  Google Scholar 

  • Ueda, H., & Matsushita, Y. (2009). Anti-opioid action of glutamate-NMDA receptor systems underlying morphine analgesic tolerance. Masui, 58, 1136–1142.

    PubMed  Google Scholar 

  • Urani, A., Romieu, P., Roman, F. J., Yamada, K., Noda, Y., Kamei, H., et al. (2004). Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein. European Journal of Pharmacology, 486, 151–161.

    Article  PubMed  CAS  Google Scholar 

  • Urosevic, M., Oberholzer, P. A., Maier, T., Hafner, J., Laine, E., Slade, H., et al. (2004). Imiquimod treatment induces expression of opioid growth factor receptor: A novel tumor antigen induced by interferon-alpha? Clinical Cancer Research, 10, 4959–4970.

    Article  PubMed  CAS  Google Scholar 

  • van Ree, J. M. (1983). The influence of neuropeptides related to pro-opiomelanocortin on acquisition of heroin self-administration of rats. Life Sciences, 33, 2283–2289.

    Article  PubMed  Google Scholar 

  • van Waarde, A., Ramakrishnan, N. K., Rybczynska, A. A., Elsinga, P. H., Ishiwata, K., Nijholt, I. M., et al. (2011). The cholinergic system, sigma-1 receptors and cognition. Behavioural Brain Research, 221, 543–554.

    Article  PubMed  CAS  Google Scholar 

  • Varani, K., Calo, G., Rizzi, A., Merighi, S., Toth, G., Guerrini, R., et al. (1998). Nociceptin receptor binding in mouse forebrain membranes: Thermodynamic characteristics and structure activity relationships. British Journal of Pharmacology, 125, 1485–1490.

    Article  PubMed  CAS  Google Scholar 

  • Vassar, R. (2002). Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Advanced Drug Delivery Reviews, 54, 1589–1602.

    Article  PubMed  CAS  Google Scholar 

  • Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., et al. (1999). Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286, 735–741.

    Article  PubMed  CAS  Google Scholar 

  • Vaughan, C. W., & Christie, M. J. (1996). Increase by the ORL1 receptor (opioid receptor-like1) ligand, nociceptin, of inwardly rectifying K conductance in dorsal raphe nucleus neurones. British Journal of Pharmacology, 117, 1609–1611.

    PubMed  CAS  Google Scholar 

  • Vaughan, C. W., Connor, M., Jennings, E. A., Marinelli, S., Allen, R. G., & Christie, M. J. (2001). Actions of nociceptin/orphanin FQ and other prepronociceptin products on rat rostral ventromedial medulla neurons in vitro. Journal of Physiology, 534, 849–859.

    Article  PubMed  CAS  Google Scholar 

  • Vaughan, C. W., Ingram, S. L., Connor, M. A., & Christie, M. J. (1997). How opioids inhibit GABA-mediated neurotransmission. Nature, 390, 611–614.

    Article  PubMed  CAS  Google Scholar 

  • Venugopal, C., Demos, C. M., Rao, K. S., Pappolla, M. A., & Sambamurti, K. (2008). Beta-secretase: Structure, function, and evolution. CNS & Neurological Disorders: Drug Targets, 7, 278–294.

    Article  CAS  Google Scholar 

  • Verdejo-Garcia, A., Perez-Garcia, M., Sanchez-Barrera, M., Rodriguez-Fernandez, A., & Gomez-Rio, M. (2007). Neuroimaging and drug addiction: neuroanatomical correlates of cocaine, opiates, cannabis and ecstasy abuse. Revista de neurologia, 44, 432–439.

    PubMed  CAS  Google Scholar 

  • Vogel, J., Anand, V. S., Ludwig, B., Nawoschik, S., Dunlop, J., & Braithwaite, S. P. (2009). The JNK pathway amplifies and drives subcellular changes in tau phosphorylation. Neuropharmacology, 57, 539–550.

    Article  PubMed  CAS  Google Scholar 

  • Walton, H. S., & Dodd, P. R. (2007). Glutamate-glutamine cycling in Alzheimer’s disease. Neurochemistry International, 50, 1052–1066.

    Article  PubMed  CAS  Google Scholar 

  • Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H., & Hurd, Y. L. (2006). Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use. Pharmacogenomics Journal, 6, 255–264.

    Article  PubMed  CAS  Google Scholar 

  • Wang, Y. Q., Wang, S. B., Ma, J. L., Guo, J., Fang, Q., Sun, T., et al. (2011). Neuropeptide FF receptor antagonist, RF9, attenuates the fever induced by central injection of LPS in mice. Peptides, 32, 702–706.

    Article  PubMed  CAS  Google Scholar 

  • Ward, H. G., Nicklous, D. M., Aloyo, V. J., & Simansky, K. J. (2006). Mu-opioid receptor cellular function in the nucleus accumbens is essential for hedonically driven eating. European Journal of Neuroscience, 23, 1605–1613.

    Article  PubMed  Google Scholar 

  • Wen, H., Lu, Y., Yao, H., & Buch, S. (2011). Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: Implication for vascular permeability. PLoS ONE, 6, e21707.

    Article  PubMed  CAS  Google Scholar 

  • Werling, L. L., Brown, S. R., & Cox, B. M. (1986). Effects of prior exposure to morphine on the opioid inhibition of the stimulated release of [3H]norepinephrine from guinea pig cortex slices. NIDA Research Monograph, 75, 587–590.

    PubMed  CAS  Google Scholar 

  • Werling, L. L., Brown, S. R., & Cox, B. M. (1987). Opioid receptor regulation of the release of norepinephrine in brain. Neuropharmacology, 26, 987–996.

    Article  PubMed  CAS  Google Scholar 

  • Werling, L. L., McMahon, P. N., & Cox, B. M. (1988). Selective tolerance at mu and kappa opioid receptors modulating norepinephrine release in guinea pig cortex. Journal of Pharmacology and Experimental Therapeutics, 247, 1103–1106.

    PubMed  CAS  Google Scholar 

  • Werling, L. L., McMahon, P. N., Portoghese, P. S., Takemori, A. E., & Cox, B. M. (1989). Selective opioid antagonist effects on opioid-induced inhibition of release of norepinephrine in guinea pig cortex. Neuropharmacology, 28, 103–107.

    Article  PubMed  CAS  Google Scholar 

  • Wilson, R. S., Weir, D. R., Leurgans, S. E., Evans, D. A., Hebert, L. E., Langa, K. M., et al. (2011). Sources of variability in estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 7, 74–79.

    Google Scholar 

  • Won, J. S., Lee, J. K., Song, D. K., Huh, S. O., Jung, J. S., Kim, Y. H., et al. (2000). Cycloheximide increases proenkephalin and tyrosine hydroxylase gene expression in rat adrenal medulla. Molecular Pharmacology, 57, 1173–1181.

    PubMed  CAS  Google Scholar 

  • Wu, S. Y., Ohtubo, Y., Brailoiu, G. C., & Dun, N. J. (2003). Effects of endomorphin on substantia gelatinosa neurons in rat spinal cord slices. British Journal of Pharmacology, 140, 1088–1096.

    Article  PubMed  CAS  Google Scholar 

  • Xia, Y., & Haddad, G. G. (2001). Major difference in the expression of delta- and mu-opioid receptors between turtle and rat brain. The Journal of Comparative Neurology, 436, 202–210.

    Article  PubMed  CAS  Google Scholar 

  • Xu, H., Lu, Y. F., & Rothman, R. B. (2003). Opioid peptide receptor studies. 16. Chronic morphine alters G-protein function in cells expressing the cloned mu opioid receptor. Synapse (New York, NY), 47, 1–9.

    CAS  Google Scholar 

  • Xu, J. Y., Seyed-Mozaffari, A., Archer, S., & Bidlack, J. M. (1996). N-cyclobutylmethyl analog of normorphinone, N-CBM-TAMO: A short-term opioid agonist and long-term Mu-selective irreversible opioid antagonist. Journal of Pharmacology and Experimental Therapeutics, 279, 539–547.

    PubMed  CAS  Google Scholar 

  • Yakovleva, T., Marinova, Z., Kuzmin, A., Seidah, N. G., Haroutunian, V., Terenius, L., et al. (2007). Dysregulation of dynorphins in Alzheimer disease. Neurobiology of Aging, 28, 1700–1708.

    Article  PubMed  CAS  Google Scholar 

  • Yao, Y., Chinnici, C., Tang, H., Trojanowski, J. Q., Lee, V. M., & Pratico, D. (2004). Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis. Journal of Neuroinflammation, 1, 21.

    Article  PubMed  CAS  Google Scholar 

  • Yoburn, B. C., Purohit, V., Patel, K., & Zhang, Q. (2004). Opioid agonist and antagonist treatment differentially regulates immunoreactive mu-opioid receptors and dynamin-2 in vivo. European Journal of Pharmacology, 498, 87–96.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Donahue, R. N., Bonneau, R. H., & McLaughlin, P. J. (2011). T lymphocyte proliferation is suppressed by the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology, 216, 579–590.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Donahue, R. N., & McLaughlin, P. J. (2009). Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 297, R1154–R1161.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Donahue, R. N., Rogosnitzky, M., & McLaughlin, P. J. (2008). Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function. Experimental Biology and Medicine (Maywood), 233, 968–979.

    Article  CAS  Google Scholar 

  • Zagon, I. S., Goodman, S. R., & McLaughlin, P. J. (1993). Zeta (zeta), the opioid growth factor receptor: Identification and characterization of binding subunits. Brain Research, 605, 50–56.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., & McLaughlin, P. J. (1993). Production and characterization of polyclonal and monoclonal antibodies to the zeta (zeta) opioid receptor. Brain Research, 630, 295–302.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Ruth, T. B., Leure-duPree, A. E., Sassani, J. W., & McLaughlin, P. J. (2003). Immunoelectron microscopic localization of the opioid growth factor receptor (OGFr) and OGF in the cornea. Brain Research, 967, 37–47.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Smith, J. P., Conter, R., & McLaughlin, P. J. (2000). Identification and characterization of opioid growth factor receptor in human pancreatic adenocarcinoma. International Journal of Molecular Medicine, 5, 77–84.

    PubMed  CAS  Google Scholar 

  • Zagon, I. S., Verderame, M. F., & McLaughlin, P. J. (2002). The biology of the opioid growth factor receptor (OGFr). Brain Research. Brain Research Reviews, 38, 351–376.

    Article  PubMed  CAS  Google Scholar 

  • Zagon, I. S., Wu, Y., & McLaughlin, P. J. (1996). The opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor are present in human and mouse skin and tonically act to inhibit DNA synthesis in the epidermis. The Journal of Investigative Dermatology, 106, 490–497.

    Article  PubMed  CAS  Google Scholar 

  • Zernig, G., Issaevitch, T., Broadbear, J. H., Burke, T. F., Lewis, J. W., Brine, G. A., et al. (1995). Receptor reserve and affinity of mu opioid agonists in mouse antinociception: Correlation with receptor binding. Life Sciences, 57, 2113–2125.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J., Haddad, G. G., & Xia, Y. (2000). delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury. Brain Research, 885, 143–153.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, M., & Joo, D. T. (2008). Enhancement of spinal N-methyl-d-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology, 109, 308–317.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, J., Zhang, Y., Xin, S. M., Ma, L., & Pei, G. (1998). Attenuation of nociceptin/orphanin FQ-induced signaling by N-methyl-d-aspartate in neuronal cells. NeuroReport, 9, 631–636.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the start-up funds from Texas A&M Health Science Center to Dr. Anna Ratka.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anna Ratka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, Z., Ratka, A. Opioid System and Alzheimer’s Disease. Neuromol Med 14, 91–111 (2012). https://doi.org/10.1007/s12017-012-8180-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-012-8180-3

Keywords

Navigation