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The indirect γ-aminobutyric acid (GABA) receptor agonist gabaculine-induced loss of the righting reflex may inhibit the descending analgesic pathway.
Pharmacology Biochemistry and Behavior ( IF 3.3 ) Pub Date : 2020-09-07 , DOI: 10.1016/j.pbb.2020.173034
Yuya Ogawa 1 , Masahiro Irifune 2 , Akari Mukai 2 , Yoshitaka Shimizu 2 , Mitsuru Doi 2 , Kana Oue 1 , Mitsuhiro Yoshida 1 , Takashi Kanematsu 3 , Norimitsu Morioka 4 , Yoshihiro Nakata 4 , Norio Sakai 5
Affiliation  

In the spinal cord, γ-aminobutyric acid (GABA) interneurons play an essential role in antinociception. However, not all actions of GABA favor antinociception at the supraspinal level. We previously reported that gabaculine, which increases endogenous GABA in the synaptic clefts, induces loss of the righting reflex (LORR) that is one indicator of hypnosis, but not immobility in response to noxious stimulus. A slow pain is transmitted to the spinal cord via C fibers and evokes substance P (SP) release from their terminals. However, the antinociceptive effects of gabaculine are still unknown. Our study examined whether the analgesic effects of the opioid morphine or the α2-adrenoceptor agonist dexmedetomidine, whose actions are mediated through facilitation of the descending analgesic pathway, are affected by gabaculine-induced LORR. We also explored the effects of GABA receptor agonists on SP release from cultured dorsal root ganglion (DRG) neurons. All drugs were administered systemically to mice. To assess antinociception, loss of nociceptive response (analgesia) and immobility were evaluated. DRG cells were dissected from rats. Gabaculine produced no analgesia. Either morphine or dexmedetomidine in combination with gabaculine induced immobility; however, the doses of each drug required to induce immobility were much higher than those required to induce analgesia. Capsaicin significantly increased SP release from DRG cells, but a high concentration (1 mM) of the GABA receptor agonist muscimol, propofol, gaboxadol, or baclofen did not inhibit the capsaicin-induced SP release, suggesting that their antinociceptive effects were not through this mechanism. Thus, the gabaculine-induced LORR may inhibit the descending analgesic pathway.



中文翻译:

间接的γ-氨基丁酸(GABA)受体激动剂加巴奎林引起的扶正反射丧失可能抑制下行的镇痛途径。

在脊髓中,γ-氨基丁酸(GABA)中神经元在抗伤害感受中起重要作用。但是,并非所有GABA的作用都有助于在脊髓上水平的抗伤害感受。我们以前曾报道过,加巴奎林会增加突触裂隙中的内源性GABA,会引起扶正反射(LORR)的丧失,这是催眠的一种指标,但不能对有害刺激产生不动。缓慢的疼痛通过C纤维传递至脊髓,并引起P物质(SP)从其末端释放。然而,加巴奎林的抗伤害感受作用仍然未知。我们的研究调查是否阿片类吗啡的镇痛作用或α 2-肾上腺素受体激动剂右美托咪定的作用受加巴奎林诱导的LORR的影响,其作用是通过促进下行镇痛途径介导的。我们还探讨了GABA受体激动剂对培养的背根神经节(DRG)神经元SP释放的影响。所有药物均对小鼠全身给药。为了评估抗伤害感受,评估了伤害感受反应(镇痛)的丧失和不动。从大鼠解剖DRG细胞。加巴奎林未产生镇痛作用。吗啡或右美托咪定联合加巴奎林诱导的固定性;但是,诱导不动所需要的每种药物的剂量要比诱导镇痛所需要的剂量高得多。辣椒素可显着增加DRG细胞的SP释放,但高浓度(1 mM)的GABA受体激动剂麝香酚,异丙酚,加波沙朵或巴氯芬没有抑制辣椒素诱导的SP释放,表明它们的抗伤害感受作用不是通过这种机制实现的。因此,加巴瓜林诱导的LORR可能抑制下行的镇痛途径。

更新日期:2020-09-12
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