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

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. MNS-PC6–induced antinociception (MNS-PC6-IA) was prevented by proximal block of the median nerve with lidocaine as well 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 that MNS-PC6-IA was prevented by intravlPAG inhibition of 2-AG synthesis and was attenuated inCnr1−/−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 OX1R-initiated 2-AG retrograde disinhibition in the vlPAG. The opioid-independent characteristic of MNS-PC6–induced analgesia may provide a strategy for pain management in opioid-tolerant patients.

Median Nerve Stimulation as a Nonpharmacological Approach to Bypass Analgesic Tolerance to Morphine: A Proof-of-Concept Study in Mice

“…We have previously revealed a non-opioid analgesic mechanism that can be induced by median nerve electrostimulation (MNS) in mice. 6 The PC6 (Neiguan) acupoint, located overlying the median nerve on the anterior forearm, 69 was chosen as a standardized location to insert the acupuncture needle for MNS. We have proven that this procedure induced an analgesic effect equivalent to that induced by direct MNS in mice, and thus referred to the procedure as MNS-PC6 and MNS-PC6-induced analgesia as MNS-PC6-IA.…”

<p>Bibliometric Analysis of Research Assessing the Use of Acupuncture for Pain Treatment Over the Past 20 Years</p>

“…23,24 Furthermore, many studies, including brain imaging studies of humans and animals, have explored the neural substrates of acupuncture associated with pain control (Cluster 3: mechanism studies). 9,10 The present findings indicate that these study types together account for the majority of research on the effects and mechanisms of acupuncture treatment for pain control. Furthermore, based on our analysis of the changes in keywords by publication year, mechanism study keywords (Cluster 3) have recently become more prevalent than the keywords of the other study types ( Figure 2B).…”

“…6 Furthermore, many studies have assessed the underlying mechanisms of acupuncture analgesia in humans using brain imaging modalities, [7][8][9] and in animals using neurochemical approaches. 10,11 However, despite the rapid increase in the number of published studies and important findings regarding the effects and mechanisms of acupuncture analgesia, there has been little quantitative analysis of research on acupuncture for pain control in terms of the impact of articles (based on the citation index), authors and organizational affiliations.…”

Acupuncture decreased the risk of stroke among patients with fibromyalgia in Taiwan: A nationwide matched cohort study

“…Acupuncture also up-regulated endogenous opiates including dynorphin, endorphin, and encephalin in plasma and cerebrospinal fluid to relieve pain [49]. In addition, electroacupuncture at the PC6 acupoint of mice increased orexin A and decreased GABA levels in the ventrolateral periaqueductal gray in response to acute thermal nociceptive stimuli and mechanical allodynia [50].…”