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Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia
Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate pl...
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| Published in: | Science advances 2025-01, Vol.11 (3), p.eadp8494 |
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| creator | Neyama, Hiroyuki Wu, Yuping Nakaya, Yuka Kato, Shigeki Shimizu, Tomoko Tahara, Tsuyoshi Shigeta, Mika Inoue, Michiko Miyamichi, Kazunari Matsushita, Natsuki Mashimo, Tomoji Miyasaka, Yoshiki Dai, Yi Noguchi, Koichi Watanabe, Yasuyoshi Kobayashi, Masayuki Kobayashi, Kazuto Cui, Yilong |
| description | Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR
) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR
neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA
receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR
neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice. |
| doi_str_mv | 10.1126/sciadv.adp8494 |
| format | article |
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) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR
neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA
receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR
neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adp8494</identifier><identifier>PMID: 39813331</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Analgesia - methods ; Analgesics, Opioid - pharmacology ; Animals ; Male ; Neuralgia - metabolism ; Neurons - metabolism ; Neuroscience ; Pain - metabolism ; Periaqueductal Gray - metabolism ; Placebo Effect ; Prefrontal Cortex - metabolism ; Psychological Science ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A - metabolism ; Receptors, Opioid, mu - metabolism ; SciAdv r-articles</subject><ispartof>Science advances, 2025-01, Vol.11 (3), p.eadp8494</ispartof><rights>Copyright © 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2025 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c236t-cba4dcf8fe5a65dedda32736e14940a52963c759ca67f6f3e848ded47f78465b3</cites><orcidid>0000-0001-9656-5839 ; 0000-0001-7543-7301 ; 0000-0002-8302-1899 ; 0009-0003-2048-5252 ; 0000-0002-7807-8436 ; 0000-0003-3351-9813 ; 0009-0007-1936-6140 ; 0000-0003-1349-9886 ; 0000-0001-5398-5833 ; 0009-0007-0983-5185 ; 0000-0002-7617-2939 ; 0000-0003-2618-7152 ; 0000-0002-8792-7591 ; 0000-0003-4020-9290</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734720/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734720/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,2871,2872,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39813331$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Neyama, Hiroyuki</creatorcontrib><creatorcontrib>Wu, Yuping</creatorcontrib><creatorcontrib>Nakaya, Yuka</creatorcontrib><creatorcontrib>Kato, Shigeki</creatorcontrib><creatorcontrib>Shimizu, Tomoko</creatorcontrib><creatorcontrib>Tahara, Tsuyoshi</creatorcontrib><creatorcontrib>Shigeta, Mika</creatorcontrib><creatorcontrib>Inoue, Michiko</creatorcontrib><creatorcontrib>Miyamichi, Kazunari</creatorcontrib><creatorcontrib>Matsushita, Natsuki</creatorcontrib><creatorcontrib>Mashimo, Tomoji</creatorcontrib><creatorcontrib>Miyasaka, Yoshiki</creatorcontrib><creatorcontrib>Dai, Yi</creatorcontrib><creatorcontrib>Noguchi, Koichi</creatorcontrib><creatorcontrib>Watanabe, Yasuyoshi</creatorcontrib><creatorcontrib>Kobayashi, Masayuki</creatorcontrib><creatorcontrib>Kobayashi, Kazuto</creatorcontrib><creatorcontrib>Cui, Yilong</creatorcontrib><title>Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR
) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR
neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA
receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR
neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.</description><subject>Analgesia - methods</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Animals</subject><subject>Male</subject><subject>Neuralgia - metabolism</subject><subject>Neurons - metabolism</subject><subject>Neuroscience</subject><subject>Pain - metabolism</subject><subject>Periaqueductal Gray - metabolism</subject><subject>Placebo Effect</subject><subject>Prefrontal Cortex - metabolism</subject><subject>Psychological Science</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Receptors, Opioid, mu - metabolism</subject><subject>SciAdv r-articles</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNpVUU1r20AQXUJDHNJccwx7zMWu9lPSqQTTpIVALu0ph2W0O7InyLuqVjb431fBjnFPMzDvvXmPx9idKBZCSPste4KwW0DoK13rC3YtVWnm0ujqy9k-Y7c5vxdFIbS1RtRXbKbqSiilxDV7e-0pUcBhRZ6DH2kHI6XIU8vHNfKA2WMMFFe8B4qc4poaGtOw53mfR9zwbZzIHWHmfQcem8QhQrfCTPCVXbbQZbw9zhv25-nH7-XP-cvr86_l48vcS2XHuW9AB99WLRqwJmAIoGSpLIopVAFG1lb50tQebNnaVmGlqwmly7astDWNumHfD7r9ttlgmAyPA3SuH2gDw94lIPf_JdLardLOCVEqXcpiUng4Kgzp7xbz6DY0Be86iJi22SlhrJGmlmKCLg5QP6ScB2xPf0ThPlpxh1bcsZWJcH_u7gT_7ED9A7cWjcc</recordid><startdate>20250117</startdate><enddate>20250117</enddate><creator>Neyama, Hiroyuki</creator><creator>Wu, Yuping</creator><creator>Nakaya, Yuka</creator><creator>Kato, Shigeki</creator><creator>Shimizu, Tomoko</creator><creator>Tahara, Tsuyoshi</creator><creator>Shigeta, Mika</creator><creator>Inoue, Michiko</creator><creator>Miyamichi, Kazunari</creator><creator>Matsushita, Natsuki</creator><creator>Mashimo, Tomoji</creator><creator>Miyasaka, Yoshiki</creator><creator>Dai, Yi</creator><creator>Noguchi, Koichi</creator><creator>Watanabe, Yasuyoshi</creator><creator>Kobayashi, Masayuki</creator><creator>Kobayashi, Kazuto</creator><creator>Cui, Yilong</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9656-5839</orcidid><orcidid>https://orcid.org/0000-0001-7543-7301</orcidid><orcidid>https://orcid.org/0000-0002-8302-1899</orcidid><orcidid>https://orcid.org/0009-0003-2048-5252</orcidid><orcidid>https://orcid.org/0000-0002-7807-8436</orcidid><orcidid>https://orcid.org/0000-0003-3351-9813</orcidid><orcidid>https://orcid.org/0009-0007-1936-6140</orcidid><orcidid>https://orcid.org/0000-0003-1349-9886</orcidid><orcidid>https://orcid.org/0000-0001-5398-5833</orcidid><orcidid>https://orcid.org/0009-0007-0983-5185</orcidid><orcidid>https://orcid.org/0000-0002-7617-2939</orcidid><orcidid>https://orcid.org/0000-0003-2618-7152</orcidid><orcidid>https://orcid.org/0000-0002-8792-7591</orcidid><orcidid>https://orcid.org/0000-0003-4020-9290</orcidid></search><sort><creationdate>20250117</creationdate><title>Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia</title><author>Neyama, Hiroyuki ; Wu, Yuping ; Nakaya, Yuka ; Kato, Shigeki ; Shimizu, Tomoko ; Tahara, Tsuyoshi ; Shigeta, Mika ; Inoue, Michiko ; Miyamichi, Kazunari ; Matsushita, Natsuki ; Mashimo, Tomoji ; Miyasaka, Yoshiki ; Dai, Yi ; Noguchi, Koichi ; Watanabe, Yasuyoshi ; Kobayashi, Masayuki ; Kobayashi, Kazuto ; Cui, Yilong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c236t-cba4dcf8fe5a65dedda32736e14940a52963c759ca67f6f3e848ded47f78465b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Analgesia - methods</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Animals</topic><topic>Male</topic><topic>Neuralgia - metabolism</topic><topic>Neurons - metabolism</topic><topic>Neuroscience</topic><topic>Pain - metabolism</topic><topic>Periaqueductal Gray - metabolism</topic><topic>Placebo Effect</topic><topic>Prefrontal Cortex - metabolism</topic><topic>Psychological Science</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Receptors, Opioid, mu - metabolism</topic><topic>SciAdv r-articles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Neyama, Hiroyuki</creatorcontrib><creatorcontrib>Wu, Yuping</creatorcontrib><creatorcontrib>Nakaya, Yuka</creatorcontrib><creatorcontrib>Kato, Shigeki</creatorcontrib><creatorcontrib>Shimizu, Tomoko</creatorcontrib><creatorcontrib>Tahara, Tsuyoshi</creatorcontrib><creatorcontrib>Shigeta, Mika</creatorcontrib><creatorcontrib>Inoue, Michiko</creatorcontrib><creatorcontrib>Miyamichi, Kazunari</creatorcontrib><creatorcontrib>Matsushita, Natsuki</creatorcontrib><creatorcontrib>Mashimo, Tomoji</creatorcontrib><creatorcontrib>Miyasaka, Yoshiki</creatorcontrib><creatorcontrib>Dai, Yi</creatorcontrib><creatorcontrib>Noguchi, Koichi</creatorcontrib><creatorcontrib>Watanabe, Yasuyoshi</creatorcontrib><creatorcontrib>Kobayashi, Masayuki</creatorcontrib><creatorcontrib>Kobayashi, Kazuto</creatorcontrib><creatorcontrib>Cui, Yilong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Neyama, Hiroyuki</au><au>Wu, Yuping</au><au>Nakaya, Yuka</au><au>Kato, Shigeki</au><au>Shimizu, Tomoko</au><au>Tahara, Tsuyoshi</au><au>Shigeta, Mika</au><au>Inoue, Michiko</au><au>Miyamichi, Kazunari</au><au>Matsushita, Natsuki</au><au>Mashimo, Tomoji</au><au>Miyasaka, Yoshiki</au><au>Dai, Yi</au><au>Noguchi, Koichi</au><au>Watanabe, Yasuyoshi</au><au>Kobayashi, Masayuki</au><au>Kobayashi, Kazuto</au><au>Cui, Yilong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2025-01-17</date><risdate>2025</risdate><volume>11</volume><issue>3</issue><spage>eadp8494</spage><pages>eadp8494-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR
) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR
neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA
receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR
neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>39813331</pmid><doi>10.1126/sciadv.adp8494</doi><orcidid>https://orcid.org/0000-0001-9656-5839</orcidid><orcidid>https://orcid.org/0000-0001-7543-7301</orcidid><orcidid>https://orcid.org/0000-0002-8302-1899</orcidid><orcidid>https://orcid.org/0009-0003-2048-5252</orcidid><orcidid>https://orcid.org/0000-0002-7807-8436</orcidid><orcidid>https://orcid.org/0000-0003-3351-9813</orcidid><orcidid>https://orcid.org/0009-0007-1936-6140</orcidid><orcidid>https://orcid.org/0000-0003-1349-9886</orcidid><orcidid>https://orcid.org/0000-0001-5398-5833</orcidid><orcidid>https://orcid.org/0009-0007-0983-5185</orcidid><orcidid>https://orcid.org/0000-0002-7617-2939</orcidid><orcidid>https://orcid.org/0000-0003-2618-7152</orcidid><orcidid>https://orcid.org/0000-0002-8792-7591</orcidid><orcidid>https://orcid.org/0000-0003-4020-9290</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Analgesia - methods Analgesics, Opioid - pharmacology Animals Male Neuralgia - metabolism Neurons - metabolism Neuroscience Pain - metabolism Periaqueductal Gray - metabolism Placebo Effect Prefrontal Cortex - metabolism Psychological Science Rats Rats, Sprague-Dawley Receptors, GABA-A - metabolism Receptors, Opioid, mu - metabolism SciAdv r-articles |
| title | Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia |
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