PDF(Pubmed)
Abstract：
There is growing literature supporting cannabinoids as a potential therapeutic for pain conditions. The development of chronic pain has been associated with reduced concentrations of the endogenous cannabinoid anandamide (AEA) in the midbrain dorsal periaqueductal gray (dPAG), and microinjections of synthetic cannabinoids into the dPAG are antinociceptive. Therefore, the goal of this study was to examine the role of the dPAG in cannabinoid-mediated sensory inhibition. Given that cannabinoids in the dPAG also elicit sympathoexcitation, a secondary goal was to assess coordination between sympathetic and antinociceptive responses. AEA was microinjected into the dPAG while recording single unit activity of wide dynamic range (WDR) dorsal horn neurons (DHNs) evoked by high intensity mechanical stimulation of the hindpaw, concurrently with renal sympathetic nerve activity (RSNA), in anesthetized male rats. AEA microinjected into the dPAG decreased evoked DHN activity (n = 24 units), for half of which AEA also elicited sympathoexcitation. AEA actions were mediated by cannabinoid 1 receptors as confirmed by local pretreatment with the cannabinoid receptor antagonist AM281. dPAG microinjection of the synaptic excitant DL-homocysteic acid (DLH) also decreased evoked DHN activity (n = 27 units), but in all cases this was accompanied by sympathoexcitation. Thus, sensory inhibition elicited from the dPAG is not exclusively linked with sympathoexcitation, suggesting discrete neuronal circuits. The rostrocaudal location of sites may affect evoked responses as AEA produced sensory inhibition without sympathetic effects at 86 % of caudal compared to 25 % of rostral sites, supporting anatomically distinct neurocircuits. These data indicate that spatially selective manipulation of cannabinoid signaling could provide analgesia without potentially harmful autonomic activation.
摘要：
越来越多的文献支持大麻素作为疼痛病症的潜在治疗剂。慢性疼痛的发展与中脑背侧导水管周围灰质（dPAG）中内源性大麻素anandamide（AEA）的浓度降低有关，将合成大麻素微量注射到dPAG中具有抗伤害性。因此,本研究的目的是研究dPAG在大麻素介导的感觉抑制中的作用.鉴于dPAG中的大麻素也会引起交感神经兴奋，次要目标是评估交感神经反应和镇痛反应之间的协调性.将AEA显微注射到dPAG中，同时记录由后爪的高强度机械刺激引起的宽动态范围（WDR）背角神经元（DHN）的单个单位活动，同时伴有肾交感神经活动（RSNA），在麻醉的雄性大鼠中。微量注射到dPAG中的AEA降低了诱发的DHN活性（n=24单位），其中一半的AEA也引起交感神经兴奋。AEA作用由大麻素1受体介导,如用大麻素受体拮抗剂AM281局部预处理所证实。dPAG显微注射突触兴奋性DL-同型半胱氨酸（DLH）也降低了诱发的DHN活性（n=27个单位），但在所有情况下，这都伴随着交感神经兴奋。因此，dPAG引起的感觉抑制并不完全与交感神经兴奋有关，暗示离散的神经元回路。由于AEA在86％的尾部产生感觉抑制而没有交感神经作用，因此部位的后部位置可能会影响诱发反应，支持解剖学上不同的神经回路。这些数据表明大麻素信号的空间选择性操纵可以提供镇痛而没有潜在的有害自主神经激活。
