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To determine whether persistent pain diminishes the actions of a nicotinic acetylcholine receptor (nAChR) agonist in pain modulatory pathways, we examined the effects of epibatidine in the rostral ventromedial medulla (RVM) of rats with and without inflammatory injury induced by intraplantar injection of complete Freund\u2019s adjuvant (CFA). In uninjured rats, epibatidine produced a dose-dependent antinociception that was completely blocked by dihydro-\u03b2-erythroidine (DH\u03b2E; \u03b14\u03b22 antagonist) and partially blocked by methyllycaconitine (MLA; \u03b17 antagonist). Epibatidine reversed heat hyperalgesia when microinjected in the RVM 4 h, 4 d, or 2 weeks after CFA treatment. Although DH\u03b2E completely blocked epibatidine\u2019s antihyperalgesic effect at 4 h, at 2 weeks it elicited only partial antagonism. Methyllycaconitine was ineffective at both time points. Epibatidine\u2019s antinociceptive efficacy in the uninjured hind paw progressively declined, and it was without effect 2 weeks after CFA. Moreover, as early as 4 h after CFA, the antinociceptive effect of epibatidine was no longer antagonized by DH\u03b2E. Neither antagonist alone altered paw withdrawal latency in uninjured or CFA-treated rats, suggesting that neither \u03b14\u03b22 nor \u03b17 nAChRs are tonically active in the RVM. The<jats:italic>B<\/jats:italic><jats:sub>max<\/jats:sub>and<jats:italic>K<jats:sub>d<\/jats:sub><\/jats:italic>of \u03b14\u03b22 nAChRs in the RVM were unchanged after CFA treatment. These observations provide the first evidence of pharmacological plasticity of the actions of \u03b14\u03b22 nAChR agonists in a critical brainstem pain modulatory pathway and may in part explain why people with chronic pain smoke more than the general population.<\/jats:p>","DOI":"10.1523\/eneuro.0364-16.2017","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T01:35:46Z","timestamp":1484876146000},"page":"ENEURO.0364-16.2017","source":"Crossref","is-referenced-by-count":11,"title":["Plasticity in Brainstem Mechanisms of Pain Modulation by Nicotinic Acetylcholine Receptors in the Rat"],"prefix":"10.1523","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-1256","authenticated-orcid":false,"given":"Francis J.","family":"Jareczek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie R.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2537-0441","authenticated-orcid":false,"given":"Donna L.","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2017,1,19]]},"reference":[{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.194506"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-166272"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.04.013"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.4","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13528"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2016.01.073"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5347.77"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.7","doi-asserted-by":"crossref","first-page":"7950","DOI":"10.1523\/JNEUROSCI.23-21-07950.2003","article-title":"Roles of \u03b11- and \u03b12-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia","volume":"23","year":"2003","journal-title":"J Neurosci"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.8","doi-asserted-by":"crossref","first-page":"5426","DOI":"10.1523\/JNEUROSCI.18-14-05426.1998","article-title":"Role of the nucleus raphe magnus in antinociception produced by ABT-594: immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotonergic neurons","volume":"18","year":"1998","journal-title":"J Neurosci"},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.9","unstructured":"Centers for Disease Control and Prevention (2004) The Health Consequences of Smoking: A Report of the Surgeon General, in (Services USDoHaH ed), Office on Smoking and Health, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, GA."},{"key":"2023041302114454000_4.1.ENEURO.0364-16.2017.10","unstructured":"Centers for Disease Control and Prevention (2010) Surgeon General\u2019s Report\u2014How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. 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