Department of Physiology, Piracicaba Dental School, State University of Campinas-UNICAMP, Piracicaba, São Paulo, Brazil.
Inflammation. 2012 Feb;35(1):371-6. doi: 10.1007/s10753-011-9329-1.
In an attempt to decrease central side effects associated with the use of opioids, some strategies have been developed by targeting peripheral opioid receptors. In this context, kappa receptors are of major interest, since, in contrast to other opioid receptors, their activation is not associated with potent peripheral side effects. We have recently demonstrated that local activation of kappa opioid receptors significantly decreases formalin-induced temporomandibular joint nociception; however, whether it also decreases temporomandibular joint inflammation is not known. To address this issue, we evaluated if a specific kappa opioid receptor agonist, U50,488 (trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide hydrochloride hydrate), administered into the temporomandibular joint decreases formalin-induced plasma extravasation and neutrophil migration. Ipsilateral, but not contralateral, administration of U50,488 into the temporomandibular joint blocked formalin-induced plasma extravasation and neutrophil migration in a dose-dependent manner. This anti-inflammatory effect was reversed by the ipsilateral, but not contralateral, administration of the kappa opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). This study demonstrates that local activation of kappa opioid receptors decreases two important parameters of temporomandibular joint inflammation, that is, plasma extravasation and neutrophil migration, in a dose-dependent and antagonist-reversible manner. This anti-inflammatory effect taken together with the potent antinociceptive effect, suggests that drugs targeting peripheral kappa opioid receptors are promising for the treatment of inflammatory temporomandibular joint pain and probably, other articular pain conditions with an inflammatory basis.
为了减少与阿片类药物使用相关的中枢副作用，一些策略已经通过针对外周阿片受体来开发。在这种情况下，κ受体是主要的关注点，因为与其他阿片受体不同，其激活与强烈的外周副作用无关。我们最近证明，局部激活 κ 阿片受体可显著降低福尔马林诱导的颞下颌关节疼痛；然而，它是否也能降低颞下颌关节炎症尚不清楚。为了解决这个问题，我们评估了一种特定的 κ 阿片受体激动剂 U50,488（反式-（1S,2S）-3,4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]苯乙酰胺盐酸盐水合物），局部注射到颞下颌关节是否会降低福尔马林诱导的血浆渗出和中性粒细胞迁移。U50,488 同侧而不是对侧注射到颞下颌关节以剂量依赖性方式阻断福尔马林诱导的血浆渗出和中性粒细胞迁移。这种抗炎作用被同侧而不是对侧给予 κ 阿片受体拮抗剂 nor-BNI（nor-binaltorphimine dihydrochloride）逆转。这项研究表明，局部激活 κ 阿片受体以剂量依赖性和拮抗剂可逆转的方式降低颞下颌关节炎症的两个重要参数，即血浆渗出和中性粒细胞迁移。这种抗炎作用与强大的镇痛作用相结合，表明靶向外周 κ 阿片受体的药物有望治疗炎症性颞下颌关节疼痛，可能还有其他以炎症为基础的关节疼痛疾病。
