Rahman Wahida, Bauer Claudia S, Bannister Kirsty, Vonsy Jean-Laurent, Dolphin Annette C, Dickenson Anthony H
Department of Neuroscience, Pharmacology and Physiology, University College London, Gower Street, London, WC1E 6BT, UK.
Mol Pain. 2009 Aug 7;5:45. doi: 10.1186/1744-8069-5-45.
Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA.
Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10-100 microg/50 microl) or systemic pregabalin (0.3 - 10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG revealed a significant increase in alpha 2 delta-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged.
These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha 2 delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.
源自脑干的下行易化作用在许多慢性疼痛状态下会促进脊髓神经元的过度兴奋和行为超敏反应。我们之前已证实在神经性疼痛模型中，下行易化作用增强作用于背角神经元，并表明这使得加巴喷丁具有镇痛效果。在此，我们通过在骨关节炎（OA）大鼠模型中运用多种方法来检验该假设是否适用于其他疼痛状态，以确定：1）是否存在下行5-羟色胺（5HT）介导的易化作用；2）普瑞巴林（加巴喷丁的一种新型类似物）在该模型中是否为有效的抗伤害感受药物。此外，进行了定量聚合酶链反应实验，以分析L3 - 6背根神经节（DRG）中α2δ-1和5-HT3A亚基的信使核糖核酸（mRNA）水平，以评估这些分子底物的变化是否与昂丹司琼和普瑞巴林在OA中的药理作用有关。
通过向膝关节内注射碘乙酸钠（MIA）诱导骨关节炎。对照动物注射0.9%生理盐水。两周后进行体内电生理学实验，比较脊髓注射昂丹司琼（10 - 100微克/50微升）或全身注射普瑞巴林（0.3 - 10毫克/千克）对MIA或对照大鼠背角神经元对电、机械和热刺激的诱发反应的影响。在MIA大鼠中，昂丹司琼显著抑制对无害和有害自然诱发神经元反应的诱发反应，而在对照中仅观察到对有害诱发反应的抑制。普瑞巴林仅显著抑制MIA大鼠的神经元反应；该效应被脊髓预先注射昂丹司琼所阻断。对L3 - 6 DRG中α2δ-1和5-HT3A亚基mRNA水平的分析显示，MIA大鼠同侧L3和4 DRG中α2δ-1水平显著升高。5-HT3A亚基mRNA水平未改变。
这些数据表明下行5-羟色胺能易化作用在介导MIA大鼠的刷状和无害机械点状诱发神经元反应中起作用，提示在MIA诱导的OA疼痛中，调节低阈值诱发神经元反应的兴奋性5-羟色胺能驱动发生了适应性变化。兴奋性5-羟色胺能驱动的这种改变，连同α2δ-1 mRNA水平的增加，可能是普瑞巴林在该慢性疼痛模型中状态依赖性效应的基础。
