Department of Neuroscience, Physiology, and Pharmacology, Medical Sciences Building, University College London, Gower Street, Room G35, London, WC1E 6BT, UK.
J Pharmacol Exp Ther. 2013 Mar;344(3):696-707. doi: 10.1124/jpet.112.199489. Epub 2013 Jan 7.
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.
骨关节炎（OA）是一种慢性关节疾病，其主要症状为慢性疼痛。目前的镇痛药效果不佳，导致这种疼痛的机制也知之甚少，但可能包括局部关节变化和中枢后果。这些研究使用单胺受体药物结合行为研究和单个背角记录，检查在碘乙酸单钠 OA 疼痛模型中，去甲肾上腺素能和 5-羟色胺能抑制是否改变，以及用 5-羟色胺/去甲肾上腺素再摄取抑制剂米那普仑增加这些抑制是否能减轻伴随的过敏。在该模型的早期和晚期，米那普仑（sc）减少了行为过敏，抑制了致敏背角神经元的诱发反应。在未处理的动物和模型的早期，但不是晚期，脊髓给予α2-肾上腺素受体拮抗剂阿替美唑完全逆转了这种神经元抑制，而单独给予阿替美唑则表明晚期内源性去甲肾上腺素抑制减少。用（2R）-1-[(3-羟基苯基)磺酰基]-2-[2-(4-甲基-1-哌啶基)乙基]吡咯烷盐酸盐阻断脊髓 5-羟色胺-7 受体表明，米那普仑在晚期的作用部分是通过这些受体介导的，并且在该阶段下行 5-羟色胺能抑制增加。米那普仑作用的阿片样机制是通过纳洛酮部分逆转这些作用来指示的。这些研究表明，米那普仑在 OA 疼痛模型中具有镇痛作用，其作用通过下行 5-羟色胺能和去甲肾上腺素能以及阿片样途径产生。在该模型的过程中，这些途径的活性变化可能导致行为过敏的存在，并决定米那普仑通过哪些内源性系统发挥作用。
