title: The antinociceptive effect of milnacipran in the monosodium iodoacetate model of osteoarthritis pain and its relation to changes in descending inhibition.
abstract: Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. Early and late in the course of this model, milnacipran (s.c.) reduced behavioral hypersensitivity, and inhibited evoked responses from sensitized dorsal horn neurons. In naïve animals and the early, but not late, phase of the model, spinal administration of the α(2)-adrenoceptor antagonist atipamezole fully reversed this neuronal inhibition, whereas atipamezole administered alone revealed that endogenous noradrenergic inhibition was reduced in the late phase. Blocking spinal 5-hydroxytryptamine-7 receptors with (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride suggested that the effects of milnacipran in the late phase were partly mediated by these receptors, and that descending serotonergic inhibition was increased in this phase. An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects.
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, Medical Sciences Building, University College London, Gower Street, Room G35, London, WC1E 6BT, UK. liamburnham@gmail.com
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Burnham
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D059350:Chronic Pain / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000078764:Milnacipran; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D010003:Osteoarthritis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D003521:Cyclopropanes; D007093:Imidazoles; D000078764:Milnacipran; D009270:Naloxone; D009292:Narcotic Antagonists; D009638:Norepinephrine; D011957:Receptors, Opioid; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C104425:serotonin 7 receptor; C050701:atipamezole