Bertels Zachariah, Mangutov Elizaveta, Siegersma Kendra, Cropper Haley C, Tipton Alycia, Pradhan Amynah A
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
iScience. 2023 Jan 10;26(2):105950. doi: 10.1016/j.isci.2023.105950. eCollection 2023 Feb 17.
Opioids prescribed for pain and migraine can produce opioid-induced hyperalgesia (OIH) or medication overuse headache (MOH). We previously demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated in OIH and chronic migraine models. Here we determined if PACAP acts as a bridge between opioids and pain chronification. We tested PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated trigeminovascular pain. The PAC1 antagonist, M65, reversed chronic allodynia in a model which combines morphine with the migraine trigger, nitroglycerin. Chronic opioids also exacerbated cortical spreading depression, a correlate of migraine aura; and M65 inhibited this augmentation. hybridization showed MOR and PACAP co-expression in trigeminal ganglia, and near complete overlap between MOR and PAC1 in the trigeminal nucleus caudalis and periaqueductal gray. PACAPergic mechanisms appear to facilitate the transition to chronic headache following opioid use, and strategies targeting this system may be particularly beneficial for OIH and MOH.
用于疼痛和偏头痛治疗的阿片类药物可引发阿片类药物诱导的痛觉过敏（OIH）或药物过量使用性头痛（MOH）。我们之前证明，在OIH和慢性偏头痛模型中，垂体腺苷酸环化酶激活多肽（PACAP）表达上调。在此，我们确定PACAP是否在阿片类药物与疼痛慢性化之间起桥梁作用。我们在阿片类药物加重的三叉神经血管性疼痛新模型中测试了PACAP-PAC1受体抑制作用。PAC1拮抗剂M65在吗啡与偏头痛触发剂硝酸甘油联合使用的模型中逆转了慢性痛觉过敏。慢性阿片类药物还加剧了皮层扩散性抑制，这是偏头痛先兆的一个相关因素；而M65抑制了这种加剧作用。杂交显示MOR和PACAP在三叉神经节中共表达，且在三叉神经尾核和导水管周围灰质中MOR和PAC1几乎完全重叠。PACAP能机制似乎促进了阿片类药物使用后向慢性头痛的转变，针对该系统的策略可能对OIH和MOH特别有益。
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