α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata
Summary Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hypera...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2024-06, Vol.45 (6), p.1160-1174 |
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| container_title | Acta pharmacologica Sinica |
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| creator | Han, Yu Zhang, Jia-qi Ji, Ya-wei Luan, Yi-wen Li, Shu-yi Geng, Hui-zhen Ji, Ying Yin, Cui Liu, Su Zhou, Chun-yi Xiao, Cheng |
| description | Summary
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure. |
| doi_str_mv | 10.1038/s41401-024-01234-7 |
| format | Article |
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Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.</description><identifier>ISSN: 1671-4083</identifier><identifier>ISSN: 1745-7254</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-024-01234-7</identifier><identifier>PMID: 38438581</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Acetylcholine - metabolism ; Analgesics - pharmacology ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Capsaicin - pharmacology ; GABAergic Neurons - drug effects ; GABAergic Neurons - metabolism ; GABAergic Neurons - physiology ; Hyperalgesia - drug therapy ; Hyperalgesia - metabolism ; Immunology ; Internal Medicine ; Male ; Medical Microbiology ; Mice ; Mice, Inbred C57BL ; Nicotine - pharmacology ; Nicotinic Agonists - pharmacology ; Nicotinic Antagonists - pharmacology ; Optogenetics ; Pain Threshold - drug effects ; Pars Reticulata - drug effects ; Pars Reticulata - metabolism ; Pharmacology/Toxicology ; Receptors, Nicotinic - metabolism ; Vaccine</subject><ispartof>Acta pharmacologica Sinica, 2024-06, Vol.45 (6), p.1160-1174</ispartof><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c347t-26b523eeea6cdf31bb56e76ecdcf919bb397832477811dfb3f0154df4bbdd9473</citedby><cites>FETCH-LOGICAL-c347t-26b523eeea6cdf31bb56e76ecdcf919bb397832477811dfb3f0154df4bbdd9473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38438581$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Yu</creatorcontrib><creatorcontrib>Zhang, Jia-qi</creatorcontrib><creatorcontrib>Ji, Ya-wei</creatorcontrib><creatorcontrib>Luan, Yi-wen</creatorcontrib><creatorcontrib>Li, Shu-yi</creatorcontrib><creatorcontrib>Geng, Hui-zhen</creatorcontrib><creatorcontrib>Ji, Ying</creatorcontrib><creatorcontrib>Yin, Cui</creatorcontrib><creatorcontrib>Liu, Su</creatorcontrib><creatorcontrib>Zhou, Chun-yi</creatorcontrib><creatorcontrib>Xiao, Cheng</creatorcontrib><title>α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Summary
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.</description><subject>Acetylcholine - metabolism</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Capsaicin - pharmacology</subject><subject>GABAergic Neurons - drug effects</subject><subject>GABAergic Neurons - metabolism</subject><subject>GABAergic Neurons - physiology</subject><subject>Hyperalgesia - drug therapy</subject><subject>Hyperalgesia - metabolism</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nicotine - pharmacology</subject><subject>Nicotinic Agonists - pharmacology</subject><subject>Nicotinic Antagonists - pharmacology</subject><subject>Optogenetics</subject><subject>Pain Threshold - drug effects</subject><subject>Pars Reticulata - drug effects</subject><subject>Pars Reticulata - metabolism</subject><subject>Pharmacology/Toxicology</subject><subject>Receptors, Nicotinic - metabolism</subject><subject>Vaccine</subject><issn>1671-4083</issn><issn>1745-7254</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1u2zAQhYmgRewmuUAXBZfdKOWfRGnpGo1TwEA26ZogqZHNQCZdkloEyKVykZ6pdJRkmc3MYN6bN8CH0FdKrinh7Y8kqCC0IkxUhDIuKnmGllSKupKsFp_K3EhaCdLyBfqS0gMhnHHanaMFbwVv65Yu0dO_Z4G9syG7UnEEC8ccYsLB483q5wrirqw9TDH4hA_QO50Ba2z3YXR-VrXX4w5SmayLdnIZO4_zHnCaTMraZ6fLi13U-KhLcoTs7DTqrC_R50GPCa5e-wX6c_Prfn1bbe82v9erbWW5kLlijakZBwDd2H7g1Ji6AdmA7e3Q0c4Y3smWMyFlS2k_GD4QWot-EMb0fSckv0Df59xjDH8nSFkdXLIwjtpDmJJiHZeS1KI-WdlstTGkFGFQx-gOOj4qStSJupqpq0JdvVBXp6Nvr_mTKYjeT94wFwOfDalIfgdRPYQpFmzpo9j_KMeQYA</recordid><startdate>20240601</startdate><enddate>20240601</enddate><creator>Han, Yu</creator><creator>Zhang, Jia-qi</creator><creator>Ji, Ya-wei</creator><creator>Luan, Yi-wen</creator><creator>Li, Shu-yi</creator><creator>Geng, Hui-zhen</creator><creator>Ji, Ying</creator><creator>Yin, Cui</creator><creator>Liu, Su</creator><creator>Zhou, Chun-yi</creator><creator>Xiao, Cheng</creator><general>Springer Nature Singapore</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></search><sort><creationdate>20240601</creationdate><title>α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata</title><author>Han, Yu ; Zhang, Jia-qi ; Ji, Ya-wei ; Luan, Yi-wen ; Li, Shu-yi ; Geng, Hui-zhen ; Ji, Ying ; Yin, Cui ; Liu, Su ; Zhou, Chun-yi ; Xiao, Cheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c347t-26b523eeea6cdf31bb56e76ecdcf919bb397832477811dfb3f0154df4bbdd9473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acetylcholine - metabolism</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Capsaicin - pharmacology</topic><topic>GABAergic Neurons - drug effects</topic><topic>GABAergic Neurons - metabolism</topic><topic>GABAergic Neurons - physiology</topic><topic>Hyperalgesia - drug therapy</topic><topic>Hyperalgesia - metabolism</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nicotine - pharmacology</topic><topic>Nicotinic Agonists - pharmacology</topic><topic>Nicotinic Antagonists - pharmacology</topic><topic>Optogenetics</topic><topic>Pain Threshold - drug effects</topic><topic>Pars Reticulata - drug effects</topic><topic>Pars Reticulata - metabolism</topic><topic>Pharmacology/Toxicology</topic><topic>Receptors, Nicotinic - metabolism</topic><topic>Vaccine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Yu</creatorcontrib><creatorcontrib>Zhang, Jia-qi</creatorcontrib><creatorcontrib>Ji, Ya-wei</creatorcontrib><creatorcontrib>Luan, Yi-wen</creatorcontrib><creatorcontrib>Li, Shu-yi</creatorcontrib><creatorcontrib>Geng, Hui-zhen</creatorcontrib><creatorcontrib>Ji, Ying</creatorcontrib><creatorcontrib>Yin, Cui</creatorcontrib><creatorcontrib>Liu, Su</creatorcontrib><creatorcontrib>Zhou, Chun-yi</creatorcontrib><creatorcontrib>Xiao, Cheng</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><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Yu</au><au>Zhang, Jia-qi</au><au>Ji, Ya-wei</au><au>Luan, Yi-wen</au><au>Li, Shu-yi</au><au>Geng, Hui-zhen</au><au>Ji, Ying</au><au>Yin, Cui</au><au>Liu, Su</au><au>Zhou, Chun-yi</au><au>Xiao, Cheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2024-06-01</date><risdate>2024</risdate><volume>45</volume><issue>6</issue><spage>1160</spage><epage>1174</epage><pages>1160-1174</pages><issn>1671-4083</issn><issn>1745-7254</issn><eissn>1745-7254</eissn><abstract>Summary
Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>38438581</pmid><doi>10.1038/s41401-024-01234-7</doi><tpages>15</tpages></addata></record> |
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| subjects | Acetylcholine - metabolism Analgesics - pharmacology Animals Biomedical and Life Sciences Biomedicine Capsaicin - pharmacology GABAergic Neurons - drug effects GABAergic Neurons - metabolism GABAergic Neurons - physiology Hyperalgesia - drug therapy Hyperalgesia - metabolism Immunology Internal Medicine Male Medical Microbiology Mice Mice, Inbred C57BL Nicotine - pharmacology Nicotinic Agonists - pharmacology Nicotinic Antagonists - pharmacology Optogenetics Pain Threshold - drug effects Pars Reticulata - drug effects Pars Reticulata - metabolism Pharmacology/Toxicology Receptors, Nicotinic - metabolism Vaccine |
| title | α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata |
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