Zacky Ariffin Mohammed, Yun Ng Si, Nadia Hamzah, Koh Darrel, Loh Natasha, Michiko Naomi, Khanna Sanjay
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore.
Neurobiol Pain. 2024 Aug 3;16:100162. doi: 10.1016/j.ynpai.2024.100162. eCollection 2024 Jul-Dec.
The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.
前脑内侧隔区（MS）的神经激肽-1受体（NK1Rs）仅定位于部分投射至海马体和扣带回皮质（Cg）的胆碱能神经元上，而这两个区域都与痛觉感受有关。在本研究中，我们探讨了以下假说：在啮齿动物慢性缩窄性损伤模型（CCI）中，隔区NK1R处的神经传递和海马胆碱能机制介导了实验性神经病理性疼痛。我们的研究表明，向大鼠隔区内微量注射P物质（SP）会在未受伤的动物中诱发类似外周超敏反应（PH）的反应，而该反应会被毒蕈碱型胆碱能受体拮抗剂硫酸阿托品全身性减弱。相反，预先破坏隔区胆碱能神经元会减弱CCI模型中PH的发展，这也会阻止脊髓和前脑中痛觉感受细胞标志物的表达。同样，向隔区内微量注射NK1Rs拮抗剂L-733,060，以及向背侧海马体（dH）的不同区域双侧或单侧微量注射胆碱能受体拮抗剂阿托品或美加明，或者向Cg双侧微量注射，均可诱发抗痛觉感受。有趣的是，L-733,060的作用伴随着前脑中CCI诱导的痛觉感受细胞标志物水平的广泛降低，且这并非由行为继发引起，这表明内侧隔区NK1R处的神经传递对痛觉处理具有积极的调节作用。上述结果表明，隔区NK1R-dH胆碱能机制促进了神经病理性痛觉感受的发展和维持，该机制协同影响dH和Cg中的痛觉处理。此外，这些数据指出了一种结合抗胆碱能药物和抗NKRs的潜在疼痛调节策略。
