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

Research output: Contribution to journalArticle

Abstract

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
Volume115
Issue number45
DOIs
Publication statusPublished - Nov 6 2018

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Endocannabinoids
Periaqueductal Gray
Median Nerve
Analgesia
Cannabinoid Receptors
Pain Management
gamma-Aminobutyric Acid
Opioid Analgesics
Needles
Orexin Receptors
Neurons
Acupuncture Points
Narcotic Antagonists
Cannabinoids
PC6 extract
Hyperalgesia
Acupuncture
Lidocaine
Electric Stimulation
Hot Temperature

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Median nerve stimulation induces analgesia via orexininitiated endocannabinoid disinhibition in the periaqueductal gray. / Chen, Yi Hung; Lee, Hsin Jung; Lee, Ming Tatt; Wu, Ya Ting; Lee, Yen Hsien; Hwang, Ling Ling; Hung, Ming Shiu; Zimmer, Andreas; MacKie, Ken; Chiou, Lih Chu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 45, 06.11.2018, p. E10720-E10729.

Research output: Contribution to journalArticle

Chen, Yi Hung ; Lee, Hsin Jung ; Lee, Ming Tatt ; Wu, Ya Ting ; Lee, Yen Hsien ; Hwang, Ling Ling ; Hung, Ming Shiu ; Zimmer, Andreas ; MacKie, Ken ; Chiou, Lih Chu. / Median nerve stimulation induces analgesia via orexininitiated endocannabinoid disinhibition in the periaqueductal gray. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 45. pp. E10720-E10729.
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AU - Wu, Ya Ting

AU - Lee, Yen Hsien

AU - Hwang, Ling Ling

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N2 - 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.

AB - 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.

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