Differential desensitization of μ‐ and δ‐ opioid receptors in selected neural pathways following chronic morphine treatment

• Published in: British journal of pharmacology 1996-01, Vol.117 (1), p.161-169
• Main Authors: Noble, Florence, Cox, Brian M.
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; adenylyl cyclase; Adenylyl Cyclases - metabolism; Aminobutyrates - pharmacology; Analgesics; Analgesics - pharmacology; Animals; Biological and medical sciences; Brain - drug effects; Brain - physiopathology; Caudate Nucleus - drug effects; Caudate Nucleus - physiopathology; Caudate‐putamen; chronic treatment; desensitization; Enkephalin, Ala-MePhe-Gly; Enkephalin, D-Penicillamine (2,5); Enkephalins - pharmacology; Glutamic Acid - pharmacology; Male; Medical sciences; morphine; Morphine - pharmacology; Morphine Dependence - physiopathology; Naloxone; Narcotic Antagonists; Neuropharmacology; nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - physiopathology; Oligopeptides - pharmacology; opioid receptors; periaqueductal gray; Periaqueductal Gray - drug effects; Periaqueductal Gray - physiopathology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - drug effects; Receptors, Opioid, mu - drug effects; Serotonin Receptor Agonists - pharmacology; Substance Withdrawal Syndrome; thalamus; Thalamus - drug effects; Thalamus - physiopathology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15169.x

1 Morphine produces a plethora of pharmacological effects and its chronic administration induces several side‐effects. The cellular mechanisms by which opiates induce these side‐effects are not fully understood. Several studies suggest that regulation of adenylyl cyclase activity by opioids and other transmitters plays an important role in the control of neural function. 2 The aim of this study was to evaluate desensitization of μ‐ and δ‐ opioid receptors, defined as a reduced ability of opioid agonists to inhibit adenylyl cyclase activity, in four different brain structures known to be involved in opiate drug actions: caudate putamen, nucleus accumbens, thalamus and periaqueductal gray (PAG). Opiate regulation of adenylyl cyclase in these regions has been studied in control and morphine‐dependent rats. 3 The chronic morphine treatment used in the present study (subcutaneous administration of 15.4 mg morphine/rat/day for 6 days via osmotic pump) induced significant physical dependence as indicated by naloxone‐precipitated withdrawal symptoms. 4 Basal adenylyl cyclase in the four brain regions was not modified by this chronic morphine treatment. In the PAG and the thalamus, a desensitization of μ‐ and δ‐opioid receptors was observed, characterized by a reduced ability of Tyr‐D‐Ala‐Gly‐(NMe)Phe‐Gly‐ol (DAMGO; μ), Tyr‐D‐Pen‐Gly‐Phe‐D‐Pen(DPDPE; δ) and [D‐Ala2]‐deltorphin‐II (DT‐II; μ) to inhibit adenylyl cyclase, activity following chronic morphine treatment. 5 The opioid receptor desensitization in PAG and thalamus appeared to be heterologous since the metabotropic glutamate receptor agonists, L‐AP4 and glutamate, and the 5‐hydroxytryptamine (5‐HT)1A receptor agonist, R(+)‐8‐hydroxy‐2‐(di‐n‐propylamino)tetralin hydrobromide (8‐OH‐DPAT), also showed reduced inhibition of adenylyl cyclase activity following chronic morphine treatment. 6 In the nucleus accumbens and the caudate putamen, desensitization of δ‐opioid receptor‐mediated inhibition without modification of μ‐opioid receptor‐mediated inhibition was observed. An indirect mechanism probably involving dopaminergic systems is proposed to explain the desensitization of δ‐mediated responses and the lack of μ‐opioid receptor desensitization after chronic morphine treatment in caudate putamen and nucleus accumbens. 7 These results suggest that adaptive responses occurring during chronic morphine administration are not identical in all opiate‐sensitive neural populations.