Elsevier

Peptides

Volume 12, Issue 1, January–February 1991, Pages 151-160
Peptides

Article
Upregulation of the opioid receptor complex by the chronic administration of morphine: A biochemical marker related to the development of tolerance and dependence

https://doi.org/10.1016/0196-9781(91)90182-OGet rights and content

Abstract

Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the “resolving power” of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6β-fluoronaltrexone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible μ-receptor antagonist, β-funaltrexamine (β-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, β-FNA failed to upregulate opioid receptors and 2) both β-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrexone-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at β-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine.

References (83)

  • J.W. Holaday et al.

    Repeated electroconvulsive shock or chronic morphine increases the number of 3H-D-ala2,D-leu5-enkephalin binding sites in rat brain

    Life Sci.

    (1982)
  • A.J. Kastin et al.

    Tyr-MIF-1 acts as an opiate antagonist in the tail-flick test

    Pharmacol. Biochem. Behav.

    (1984)
  • M. Kavaliers et al.

    IgG from antiserum against endogenous mammalian FRMF-NH2-related peptides augments morphine- and stress-induced analgesia in mice

    Peptides

    (1989)
  • A. Kruszewska et al.

    The role of central serotoninergic neurotransmission in the morphine abstinence syndrome in rats

    Drug Alcohol Depend.

    (1983)
  • N.M. Lee et al.

    Opiate and peptide interaction: Effect of enkephalins on morphine analgesia

    Eur. J. Pharmacol.

    (1980)
  • H.H. Loh et al.

    Inhibition of morphine tolerance and physical dependence development and brain serotonin synthesis by cyclohexamide

    Biochem. Pharmacol.

    (1969)
  • D.H. Malin et al.

    FMRF-NH2-like mammalian octapeptide: Possible role in opiate dependence and abstinence

    Peptides

    (1990)
  • E.J. Nestler et al.

    Regulation of G proteins by chronic morphine in the rat locus coeruleus

    Brain Res.

    (1989)
  • N.F. Rogers et al.

    Morphine-induced opioid receptor down-regulation detected in intact adult rat brain cells

    Eur. J. Pharmacol.

    (1986)
  • R.B. Rothman et al.

    Multidimensional analysis of ligand binding data: Application to opioid receptors

    Neuropeptides

    (1983)
  • R.B. Rothman et al.

    Preparation of rat brain membranes greatly enriched with either type-I-delta or type-II-delta opiate binding sites using site directed alkylating agents

    Neuropeptides

    (1984)
  • R.B. Rothman et al.

    Chronic administration of morphine and naltrexone up-regulate opioid binding sites labeled by 3H[D-ala2-MePhe4,Gly-ol5]enkephalin: Evidence for two mu binding sites

    Eur. J. Pharmacol.

    (1989)
  • R.B. Rothman et al.

    Tritiated-6-beta-fluoro-6-desoxy-oxymorphone ([3H]FOXY): A new ligand and photoaffinity probe for the mu opioid receptors

    Neuropeptides

    (1988)
  • R.B. Rothman et al.

    Morphine tolerance increases mu-noncompetitive delta binding sites

    Eur. J. Pharmacol.

    (1986)
  • R.B. Rothman et al.

    Chronic morphine up-regulates a mu-opiate binding site labeled by 3H-cycloFOXY: A novel opiate antagonist suitable for positron emission tomography

    Eur. J. Pharmacol.

    (1987)
  • K.F. Shen et al.

    Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture

    Brain Res.

    (1989)
  • A.E. Takemori et al.

    The irreversible narcotic antagonistic and reversible agonistic properties of the fumaramate methyl ester derivative of naltrexone

    Eur. J. Pharmacol.

    (1981)
  • F.C. Tortella et al.

    The anticonvulsant effects of DADL are primarily mediated by activation of delta opioid receptors: Interaction between delta and mu-receptor antagonists

    Life Sci.

    (1985)
  • J.L. Vaught et al.

    Mu and delta receptors: Their role in analgesia and in the differential effects of opioid peptides on analgesia

    Life Sci.

    (1982)
  • S.J. Ward et al.

    Opioid receptor binding characteristics of the nonequilibrium mu antagonist, beta-funaltrexamine (beta-FNA)

    Eur. J. Pharmacol.

    (1985)
  • B.C. Yoburn et al.

    Increased analgesic potency of morphine and increased brain opioid binding sites in the rat following chronic naltrexone treatment

    Life Sci.

    (1985)
  • J.E. Zadina et al.

    Chronic, but not acute, administration of morphine alters antiopiate (tyr-MIF-1) binding sites in rat brain

    Life Sci.

    (1989)
  • J. Blasig et al.

    Central serotonergic mechanisms and development of morphine dependence

    Drug Alcohol Depend.

    (1976)
  • T.P. Caruso et al.

    Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine

    J. Pharmacol. Exp. Ther.

    (1980)
  • C. Chavkin et al.

    Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus

  • H.Oj. Collier

    A general therory of the genesis of drug dependence by induction of receptors

    Nature

    (1965)
  • P.C. Contreras et al.

    Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone

    J. Pharmacol. Exp. Ther.

    (1984)
  • I. Creese et al.

    Receptor adaptations to centrally administered drugs

    Annu. Rev. Pharmacol. Toxicol.

    (1981)
  • R. D'Amato et al.

    Multiple opiate receptors in endotoxic shock: Evidence for delta involvement and mu-delta interactions in vivo

  • V.P. Dole

    Implications of methadone maintenance for theories of narcotic addiction

    JAMA

    (1988)
  • A.I. Faden et al.

    Comparison of thyrotropin-releasing hormone (TRH), naloxone, and dexamethasone treatments in experimental spinal injury

    Neurology

    (1983)
  • Cited by (58)

    • ‘Not at all what I had expected’: Discontinuing treatment with extended-release naltrexone (XR-NTX): A qualitative study

      2022, Journal of Substance Abuse Treatment
      Citation Excerpt :

      Studies have proposed that prolonged opioid use, and thus continued exposure to mu agonists, can result in kappa receptor system overdrive (Banks, 2020; Chavkin & Koob, 2016). This overdrive may lead to dysphoric mood states, which may be part of a prolonged abstinence reaction, symptoms which may be further increased by naltrexone mu opioid receptor blockade (Rothman, 1992; Rothman et al., 1991). Participants who tested the blockade with buprenorphine may have achieved an effect where buprenorphine reinforced NTX’ weak kappa and delta antagonism, producing an anti-depressant effect (Ehrich et al., 2015; Fava et al., 2020; Karp et al., 2014; McCann, 2008), which research has suggested affects dysphoric mood and opioid-seeking behavior associated with prolonged opioid withdrawal (Gerra et al., 2006; Rothman et al., 2000).

    • Attenuation of morphine-induced dependence and tolerance by ceftriaxone and amitriptyline in mice

      2014, Acta Anaesthesiologica Taiwanica
      Citation Excerpt :

      Between-system adaptations, such as the pain facilitatory systems (opiate-activated opponent systems), also play an important role in the development of opioid-induced tolerance and dependence.5–8 The activation of the ionotropic N-methyl-d-aspartate (NMDA) subtype of glutamate receptors has been implicated in the development of morphine analgesic tolerance and dependence.7,9–11 Chronic opioid treatment resulted in the activation of protein kinase C and translocation that phosphorylates the NMDA receptor-gated Ca channel, leading to potentiation of NMDA receptor activity.

    • Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action

      2013, Journal of Biological Chemistry
      Citation Excerpt :

      Both agonists and antagonists can up-regulate opioid receptors at the protein level through promoting correct conformation or folding of the receptor proteins by escaping the ERAD pathway (60–64). Similar observations were made as early as 1973, when it was reported that administration of opiates in vivo increased opioid receptor binding in the brain by as much as 70% with a concomitant enhanced sensitivity toward opioids (65–69). Presumably, the single TM variants act through a physical association with the full-length variant, supported by our evidence that they can physically associate.

    • Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

      2007, Brain Research
      Citation Excerpt :

      The effects of chronic morphine administration on MOP-binding site density have also been investigated in animal brain and brain regions. These studies produced all possible changes in MOP density, namely, up-regulation (Besse et al., 1992; Brady et al., 1989; Fabian et al., 2002, 2003; Holaday et al., 1982; Ray et al., 2004; Rothman et al., 1991; Schmidt et al., 2003; Vigano et al., 2003), down-regulation (Bhargava and Gulati, 1990; Meuser et al., 2003; Werling et al., 1989) or no change (Polastron et al., 1994; Stafford et al., 2001; Turchan et al., 1999). Some of these results appear to be regional differences, but others, performed on whole brain or the same regions of the same animal, appear to be discrepancies between different laboratories.

    • Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study

      2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    View all citing articles on Scopus
    View full text