Kawashima Hiroki, Waddington John L, Saigusa Tadashi
Department of Pharmacology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland.
Eur J Neurosci. 2025 Jul;62(1):e70192. doi: 10.1111/ejn.70192.
We have shown using isolated C-fiber-like neurons that chronic pain may reduce orexinergic neural activity and that the nucleus accumbens, a major terminal area of the mesolimbic dopaminergic system, contains OX-receptors, a subtype of orexin receptors that inhibits accumbal basal dopamine efflux. It has been suggested that stimulation of OX receptors in the brain may suppress chronic pain. To investigate how chronic pain affects orexin receptor-mediated changes in accumbal dopaminergic neural activity, we analyzed the effects of intra-accumbal infusion of orexin receptor ligands on accumbal dopamine efflux in rats using in vivo microdialysis. To experimentally induce two types of chronic pain, i.e., inflammatory and neuropathic pain, we performed, respectively, intra-plantar injection of the proinflammatory compound carrageenan into the hind paws and sciatic nerve ligation. Decreased paw withdrawal threshold following carrageenan treatment or sciatic nerve ligation was inhibited by morphine. However, meloxicam, a nonsteroidal anti-inflammatory drug, inhibited these changes in carrageenan-treated rats but not in those with sciatic nerve ligation. Neither carrageenan injection nor sciatic nerve ligation altered basal accumbal dopamine efflux. Both in carrageenan-treated and in sciatic nerve-ligated rats, the OX- and OX-receptor antagonist MK-4305 and OX-receptor antagonist EMPA-induced increase in accumbal dopamine efflux was reduced, as compared to their respective controls. The OX-receptor agonist orexin-B counteracted the EMPA-induced increase in dopamine efflux both in carrageenan-treated and in sciatic nerve-ligated rats. These results suggest that inflammatory and neuropathic pain each lead to decreased stimulation of accumbal OX-receptors by their endogenous agonists, orexin-A and/or orexin-B, thereby inhibiting dopamine efflux.
我们利用分离出的类C纤维神经元表明，慢性疼痛可能会降低食欲素能神经活动，并且伏隔核作为中脑边缘多巴胺能系统的一个主要终末区域，含有OX受体，这是食欲素受体的一种亚型，可抑制伏隔核基础多巴胺外流。有人提出，刺激大脑中的OX受体会抑制慢性疼痛。为了研究慢性疼痛如何影响食欲素受体介导的伏隔核多巴胺能神经活动变化，我们使用体内微透析分析了向大鼠伏隔核内注射食欲素受体配体对伏隔核多巴胺外流的影响。为了通过实验诱导两种类型的慢性疼痛，即炎性疼痛和神经性疼痛，我们分别在大鼠后爪足底注射促炎化合物角叉菜胶和进行坐骨神经结扎。角叉菜胶处理或坐骨神经结扎后爪退缩阈值的降低被吗啡抑制。然而，非甾体抗炎药美洛昔康抑制了角叉菜胶处理大鼠的这些变化，但对坐骨神经结扎大鼠无效。角叉菜胶注射和坐骨神经结扎均未改变伏隔核基础多巴胺外流。与各自的对照组相比，在角叉菜胶处理的大鼠和坐骨神经结扎的大鼠中，OX1和OX2受体拮抗剂MK-4305以及OX2受体拮抗剂EMPA诱导的伏隔核多巴胺外流增加均减少。OX2受体激动剂食欲素B抵消了EMPA在角叉菜胶处理的大鼠和坐骨神经结扎的大鼠中诱导的多巴胺外流增加。这些结果表明，炎性疼痛和神经性疼痛均导致内源性激动剂食欲素A和/或食欲素B对伏隔核OX受体的刺激减少，从而抑制多巴胺外流。
