Spinal mechanisms underlying A-85380-induced effects on acute thermal pain

Systemic administration of nicotinic receptor (nAChR) agonists is antinocic eptive in models of acute pain whereas their intrathecal (i.t.) administrat ion has been reported to be antinociceptive, nociceptive or without effect. It has been hypothesized that the action induced is dependent upon the sub type and location of the nAChR activated. In addition, there is considerabl e evidence that nAChR ligand-induced antinociception is mediated by other n eurotransmitter systems via descending pathways from the brainstem to the s pinal cord. The present study investigated the effects of i.t. and systemic administration of A-85380, a novel nAChR agonist, in the paw withdrawal mo del of acute thermal pain in the rat. Given i.t., A-85380 (1 and 10 nmol/ra t) decreased the latency to paw withdrawal by 2-4 s. This pronociception wa s accompanied by a spontaneous flinching behavior. Both of these effects we re differentially blocked by i.t. pretreatment with the nAChR antagonists m ecamylamine (10 nmol)>MLA (100 nmol)>DH beta E (50% with 1000 nmol) but not by alpha-bungarotoxin (0% at 0.63 nmol). Given systemically, A-85380 (0.56 mu mol/kg, i.p.) induced antinociception as indicated by an increased late ncy to paw withdrawal, an effect differentially altered by i.t. pretreatmen t with monoaminergic antagonists (100 nmol/rat). While mecamylamine and pra zosin had no effect, scopolamine, methysergide and MDL 72222 partially anta gonized 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 significan tly increased following the systemic administration of A-85380. Together th ese data suggest that the nociceptive properties of spinally administered n AChR agents are not mediated by either an alpha(4)beta(2) or an alpha(7) su btype nAChR, whereas the antinociceptive properties of systemically-adminis tered nAChR agents are mediated by descending noradrenergic, serotonergic a nd muscarinic inhibitory pathways. (C) 2000 Elsevier Science B.V. All right s reserved.