Spinal mechanisms underlying A-85380-induced effects on acute thermal pain.
Systemic administration of nicotinic receptor (nAChR) agonists is antinociceptive in models of acute pain whereas their intrathecal (i. t.) administration has been reported to be antinociceptive, nociceptive or without effect. It has been hypothesized that the action induced is dependent upon the subtype and location of the nAChR activated. In addition, there is considerable evidence that nAChR ligand-induced antinociception is mediated by other neurotransmitter systems via descending pathways from the brainstem to the spinal cord. The present study investigated the effects of i. t. and systemic administration of A-85380, a novel nAChR agonist, in the paw withdrawal model of acute thermal pain in the rat. Given i.t. , A-85380 (1 and 10 nmol/rat) decreased the latency to paw withdrawal by 2-4 s. This pronociception was accompanied by a spontaneous flinching behavior. Both of these effects were differentially blocked by i.t. pretreatment with the nAChR antagonists mecamylamine (10 nmol)>MLA (100 nmol)>DHbetaE (50% with 1000 nmol) but not by alpha-bungarotoxin (0% at 0.63 nmol). Given systemically, A-85380 (0.56 micromol/kg, i.p.) induced antinociception as indicated by an increased latency to paw withdrawal, an effect differentially altered by i.t. pretreatment with monoaminergic antagonists (100 nmol/rat). While mecamylamine and prazosin had no effect, scopolamine, methysergide and MDL 72222 partially antagonized and idazoxan completely antagonized A-85380-induced antinociception. Finally, as measured by in vivo microdialysis, levels of 5-HT, but not NE, in the i.t. space of the lumber region of the spinal cord were significantly increased following the systemic administration of A-85380. Together these data suggest that the nociceptive properties of spinally administered nAChR agents are not mediated by either an alpha(4)beta(2) or an alpha(7) subtype nAChR, whereas the antinociceptive properties of systemically-administered nAChR agents are mediated by descending noradrenergic, serotonergic and muscarinic inhibitory pathways.
Abbott Laboratories, D47W, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. lynne.e.rueter@abbott.com
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Rueter
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Meyer
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Decker
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D002038:Bungarotoxins / Q000008:administration & dosage; D003000:Clonidine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008161:Lumbosacral Region; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D009638:Norepinephrine / Q000378:metabolism; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000008:administration & dosage; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*
C104288:A 85380; D000316:Adrenergic alpha-Agonists; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D018727:Muscarinic Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D012702:Serotonin Antagonists; D012701:Serotonin; D008464:Mecamylamine; C082748:epibatidine; D003000:Clonidine; D009638:Norepinephrine