Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray.

作者: Yi-Hung Chen , Hsin-Jung Lee , Ming Tatt Lee , Ya-Ting Wu , Yen-Hsien Lee

DOI: 10.1073/PNAS.1807991115

关键词: Internal medicineEndocannabinoid systemStimulationOrexinOpioid receptorPeriaqueductal grayEndocrinologyMedicineNociceptionCannabinoidOrexin-A

摘要: Adequate pain management remains an unmet medical need. We previously revealed opioid-independent analgesic mechanism mediated by orexin 1 receptor (OX1R)-initiated 2-arachidonoylglycerol (2-AG) signaling in the ventrolateral periaqueductal gray (vlPAG). Here, we found that low-frequency median nerve stimulation (MNS) through acupuncture needles at PC6 (Neiguan) acupoint (MNS-PC6) induced antinociceptive effect engaged this mechanism. In mice, MNS-PC6 reduced acute thermal nociceptive responses and neuropathy-induced mechanical allodynia, increased number of c-Fos–immunoreactive hypothalamic neurons, led to higher A lower GABA levels vlPAG. Such were not seen mice with needle insertion only or electrical lateral deltoid, a nonmedian nerve-innervated location. Directly stimulating surgically exposed also vlPAG levels. MNS-PC6–induced antinociception (MNS-PC6-IA) was prevented proximal block lidocaine as well systemic intravlPAG injection antagonist OX1Rs cannabinoid receptors (CB1Rs) but opioid antagonists. Systemic blockade CB1Rs restored after MNS-PC6. (2-AG)-dependent implicated observations MNS-PC6-IA inhibition 2-AG synthesis attenuated Cnr1−/− mice. These findings suggest PC6-targeting MNS activates releasing orexins induce analgesia CB1R-dependent cascade OX1R-initiated retrograde disinhibition The characteristic may provide strategy for opioid-tolerant patients.

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