title: A cholinergic interaction in alpha 2 adrenoceptor-mediated antinociception in sheep.
abstract: Intraspinal administration of alpha 2 adrenergic agonists produces analgesia, but clinical application of these agents is limited by dose-dependent sedation and hypotension. Recently, neostigmine has been demonstrated to counteract hypotension in sheep and enhance antinociception to tail flick in rats from spinally administered alpha 2 adrenergic agonists. We investigated this spinal interaction further in chronically prepared, conscious sheep, testing antinociception with a mechanical pressure stimulus on the forelimb. Clonidine produced dose-dependent antinociception which was antagonized by idazoxan and enhanced by neostigmine, although it was unaltered by methylatropine. Clonidine increased acetylcholine in cerebrospinal fluid, an effect potentiated by physostigmine and blocked by idazoxan. The highly lipid-soluble alpha 2 adrenergic agonists dexmedetomidine and clonidine produced antinociception, whereas the poorly lipid-soluble ST-91 (2,[2,6-diethylphenylamino]-2-imidazoline) produced antinociception only at much larger doses and did not affect cerebrospinal fluid levels of acetylcholine. In human volunteers, epidurally administered clonidine increased cerebrospinal fluid acetylcholine levels at the time of peak analgesia. These results support the existence of an interaction between alpha 2 adrenergic and cholinergic mechanisms of analgesia at the spinal level and underscore the importance of lipid solubility in the actions of spinally administered drugs in sheep.
authors.affiliation: Department of Anesthesia, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: D J
authors.initials: DJ
authors.lastname: Detweiler
authors.forename: J C
authors.initials: JC
authors.lastname: Eisenach
authors.forename: C
authors.initials: C
authors.lastname: Tong
authors.forename: C
authors.initials: C
authors.lastname: Jackson
mesh_terms: D000109:Acetylcholine / Q000134:cerebrospinal fluid; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D005260:Female; D006801:Humans; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology; D007278:Injections, Spinal; D020926:Medetomidine; D011950:Receptors, Cholinergic / Q000187:drug effects*; D012756:Sheep
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D004146:Dioxanes; D007093:Imidazoles; D011950:Receptors, Cholinergic; C011266:ST 91; D003000:Clonidine; D020926:Medetomidine; D000109:Acetylcholine; D019329:Idazoxan