Median nerve stimulation induces analgesia via orexininitiated endocannabinoid disinhibition in the periaqueductal gray

Yi Hung Chen, Hsin Jung Lee, Ming Tatt Lee, Ya Ting Wu, Yen Hsien Lee, Ling Ling Hwang, Ming Shiu Hung, Andreas Zimmer, Ken MacKie, Lih Chu Chiou

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39 Citations (Scopus)


Adequate pain management remains an unmet medical need. We previously revealed an 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 the PC6 (Neiguan) acupoint (MNS-PC6) induced an antinociceptive effect that engaged this mechanism. In mice, MNS-PC6 reduced acute thermal nociceptive responses and neuropathy-induced mechanical allodynia, increased the number of c-Fos-immunoreactive hypothalamic orexin neurons, and led to higher orexin A and lower GABA levels in the vlPAG. Such responses were not seen in mice with PC6 needle insertion only or electrical stimulation of the lateral deltoid, a nonmedian nerve-innervated location. Directly stimulating the surgically exposed median nerve also increased vlPAG orexin A levels. MNSPC6- induced antinociception (MNS-PC6-IA) was prevented by proximal block of themedian nervewith lidocaine aswell as by systemic or intravlPAG injection of an antagonist of OX1Rs or cannabinoid 1 receptors (CB1Rs) but not by opioid receptor antagonists. Systemic blockade of OX1Rs or CB1Rs also restored vlPAG GABA levels after MNS-PC6. A cannabinoid (2-AG)-dependent mechanism was also implicated by the observations thatMNS-PC6-IAwas prevented by intravlPAG inhibition of 2-AG synthesis and was attenuated in Cnr1-/- mice. These findings suggest that PC6-targeting low-frequency MNS activates hypothalamic orexin neurons, releasing orexins to induce analgesia through a CB1R-dependent cascade mediated by OX1Rinitiated 2-AG retrograde disinhibition in the vlPAG. The opioidindependent characteristic of MNS-PC6-induced analgesia may provide a strategy for pain management in opioid-tolerant patients.

Original languageEnglish
Pages (from-to)E10720-E10729
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
Publication statusPublished - Nov 6 2018


  • Analgesia
  • Endocannabinoid
  • Median nerve stimulation
  • Orexin
  • Periaqueductal gray

ASJC Scopus subject areas

  • General


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