Spinal delta-opioid receptors mediate suppression of systemic SNC80 on excitability of the flexor reflex in normal and inflamed rat.
Due to low central nervous system (CNS) bioavailability of delta-opioid peptides, little is known about the effect of systemic administration of delta-opioid receptor ligands. The present study examined the effect of non-peptidergic delta-opioid receptor agonists, (+)-4-[(alphaR)-alpha-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) and (-)dibenzoyl-L-tartaric acid salt (SNC86), on the activity of alpha-motoneurons in decerebrate-spinal rats. The flexor reflex was facilitated by C-afferent conditioning inputs, shown by a decrease in mechanical threshold and increase in touch- and pinch-evoked responses. Systemic administration of SNC80 (10 micromol/kg) prevented and reversed the neuronal hyperactivity. We further examined the effect of this agonist on the hypersensitivity of the flexor reflex induced by intraplantar injection of Freund's adjuvant. SNC80 dose-dependently (1, 3, 5 and 10 micromol/kg) increased the mechanical threshold and decreased touch-, pinch- and Abeta-afferent inputs-evoked responses. Similar effects were seen with SNC86 (5 micromol/kg). Pretreatment with either naloxone (20 micromol/kg, i.p.) or (Cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-14beta-ethoxy-5beta-methylindolo [2',3':6',7']morphinan-3-ol hydrochloride (SH378; 5 micromol/kg, intraarterially (i.a.)), a novel selective delta-opioid receptor antagonist, completely abolished the anti-hypersensitivity effect of SNC80. The effect of SNC80 remained following intrathecal administration of mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP; 1.5 nmol). These results indicate that systemic injection of SNC80 exerted antihypersensitivity in models of both acute and tonic nociception and these effects are mediated mainly through a spinal delta-opioid mechanism.
Cao
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Department of Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting, H4S 1Z9, St. Laurent, Quebec, Canada.
Hong
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Dray
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Perkins
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D000344:Afferent Pathways / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects*; D003213:Conditioning, Psychological; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity; D004558:Electric Stimulation; D004594:Electrophysiology; D005620:Freund's Adjuvant / Q000494:pharmacology; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009019:Morphinans / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D010879:Piperazines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013644:Tartrates / Q000494:pharmacology; D014110:Touch / Q000187:drug effects / Q000502:physiology
C435202:(cyclopropylmethyl)-6,7-dehydro-4,5-epoxy-14-ethoxy-5-methylindolo(2',3'-6',7')morphinan-3-ol; D001549:Benzamides; D007211:Indoles; D009019:Morphinans; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013644:Tartrates; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009270:Naloxone; C435201:2,3-bis(benzoyloxy)tartaric acid; D013004:Somatostatin; D005620:Freund's Adjuvant