Attenuation of the gerbil writhing response by mu-, kappa- and delta-opioids, and NK-1, -2 and -3 receptor antagonists.
Mu-, kappa- and delta-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal constriction response in mice. NK-1, -2 and -3 receptor antagonists also display activity in several visceral pain models. As the gerbil NK-1 receptor is comparable to the human receptor, we evaluated the efficacy of NK-1, -2 and -3 receptor antagonists and opioids (both alone and in combination) in the writhing test in this species. The effects of a selective L-type calcium (Ca2+) channel antagonist on the writhing response were also assessed to determine the contribution of Ca2+ channel antagonism to the antinociceptive effects of the NK-1 antagonists. Gerbils received subcutaneous injections of either the mu-opioids morphine or fentanyl, the kappa-opioid U50,488-H, the delta-opioid SNC80, NK-1 antagonists R116301, CP-96,345 or GR203040, the NK-2 antagonist SR-48968, the NK-3 antagonist SR-142801 or the Ca2+ channel antagonist nimodipine. Writhing was evoked 1 h after treatment by intraperitoneal injection of 0.2 ml 1% acetic acid solution and the frequency was recorded. Morphine, fentanyl and U50,488-H attenuated the writhing response dose dependently with complete inhibition occurring at the highest doses. SNC80 did not significantly attenuate the writhing response even at a dose of 40 mg/kg. The tachykinin NK-1 antagonists CP-96,345 and GR203040, the NK-2 antagonist SR-48968 and the NK-3 antagonist SR-142801 reduced the writhing frequency although without complete inhibition. The NK-1 antagonist R116301 displayed limited activity at doses up to 40 mg/kg. Nimodipine did not exhibit any antinociceptive efficacy in this assay. Adding the NK-1, -2 or -3 antagonists to the opioids did not improve the efficacy of the opioids. Selective NK antagonists may therefore be effective in a visceral nociception assay in gerbils but do not modulate opioid action.
Gallantine
Elizabeth L
EL
R&D, PRD Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Meert
Theo F
TF
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000005:Abdomen; D019342:Acetic Acid; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology; D000440:Butanols / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D005849:Gerbillinae; D008293:Malates; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology
D000701:Analgesics, Opioid; D001713:Biphenyl Compounds; D000440:Butanols; D002121:Calcium Channel Blockers; D008293:Malates; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; C400708:R116301; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013777:Tetrazoles; C097591:(2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D019342:Acetic Acid; D005283:Fentanyl; C066892:CP 96345