{"corpus_id":53037961,"paper_sha":"eb4995e3b18a8f29645cdb159b58fdb0ea65b33d","doi":"10.1073/pnas.1807991115","arxiv_id":null,"pmid":30348772,"pmcid":"PMC6233149","mag_id":2897151902,"dblp_id":null,"acl_id":null,"title":"Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray","year":2018,"publication_date":"2018-10-22","venue":"Proceedings of the National Academy of Sciences of the United States of America","journal":{"name":"Proceedings of the National Academy of Sciences","pages":"E10720 - E10729","volume":"115"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Extramural","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Medicine"],"reference_count":87,"citation_count":61,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Analgesia","mj":true,"ui":"D000698"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Endocannabinoids","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D063388"},{"d":"Gray Matter","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D066128"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Median Nerve","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"},{"q":"physiology","mj":true,"ui":"Q000502"}],"ui":"D008475"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Orexins","mj":false,"qs":[{"q":"pharmacology","mj":true,"ui":"Q000494"}],"ui":"D000068797"}],"chemicals":[{"n":"Endocannabinoids","ui":"D063388","reg":"0"},{"n":"Orexins","ui":"D000068797","reg":"0"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.pnas.org/content/pnas/115/45/E10720.full.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/eb4995e3b18a8f29645cdb159b58fdb0ea65b33d","s2_open_access_license":null,"s2_open_access_status":"BRONZE","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Significance Pain remains an unmet medical need due to the ineffectiveness or significant side effects of current pain therapies. Peripheral neurostimulation has been used to relieve pain for decades, but its mechanism(s) remain unsettled. Here, we established an animal model of median nerve stimulation by electrically stimulating the PC6 (Neiguan) acupoint of mice (MNS-PC6). We found MNS-PC6 can release an endogenous neuropeptide (orexin) from the hypothalamus to inhibit pain responses in mice through an endocannabinoid (an endogenous lipid functioning like chemicals from cannabis) that reduces the inhibitory (GABAergic) control in a midbrain pain-control region (the periaqueductal gray). Importantly, MNS-PC6–induced pain relief is endogenous opioid independent. Thus, MNS-PC6 may provide an alternative strategy for pain management in opioid-tolerant patients. 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 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 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.","claims":[{"public_id":"cl_12161263717c7dcb285a8ed8859012bc","status":"active","text":"Low-frequency median nerve stimulation at the PC6 acupoint reduces acute thermal nociception and neuropathy-induced mechanical allodynia in mice.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_12161263717c7dcb285a8ed8859012bc"},{"public_id":"cl_f3974383e6d57cc909ce9ce256cd35eb","status":"active","text":"Median nerve stimulation at PC6 activates hypothalamic orexin neurons and elevates orexin A while lowering GABA levels in the ventrolateral periaqueductal gray.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_f3974383e6d57cc909ce9ce256cd35eb"},{"public_id":"cl_05cf87db855e5162323de54d3f2eca99","status":"active","text":"Median nerve stimulation-induced antinociception is blocked by OX1R antagonism, CB1R antagonism, and inhibition of 2-arachidonoylglycerol synthesis, but not by opioid receptor antagonists.","confidence":0.99,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_05cf87db855e5162323de54d3f2eca99"},{"public_id":"cl_94c9c0ccb73c567a8e5f8b750f94c699","status":"active","text":"The analgesic effect depends on the median nerve and is not produced by PC6 needle insertion alone or by electrical stimulation at a nonmedian nerve-innervated site.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_94c9c0ccb73c567a8e5f8b750f94c699"},{"public_id":"cl_7a29af5a6cc758fa4f3815ff00710672","status":"active","text":"The mechanism is consistent with orexin-initiated 2-AG retrograde disinhibition in the ventrolateral periaqueductal gray.","confidence":0.93,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_7a29af5a6cc758fa4f3815ff00710672"}],"concepts":[{"public_id":"co_0c0c238005c238c9f8990b0b9dcbb192","status":"active","name":"orexin-initiated 2-arachidonoylglycerol retrograde disinhibition","description":"A signaling cascade in which orexin activation leads to 2-AG-mediated reduction of inhibitory GABAergic 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(12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_6751598ec7abf5edca32eb7c09adac39"},{"public_id":"co_71c055a0d210e0ab66495dd971418cbc","status":"active","name":"median nerve","description":"The peripheral nerve targeted by stimulation and nerve-block experiments.","types":["nerve"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_71c055a0d210e0ab66495dd971418cbc"},{"public_id":"co_727561d368b8653c4174758a343433d5","status":"active","name":"PC6 needle insertion","description":"Needle placement at PC6 without electrical stimulation.","types":["procedure"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous 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