title: Plasticity in Brainstem Mechanisms of Pain Modulation by Nicotinic Acetylcholine Receptors in the Rat.
abstract: Individuals with chronic pain may be driven to smoke more because the analgesic efficacy of nicotine diminishes. 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's adjuvant (CFA). In uninjured rats, epibatidine produced a dose-dependent antinociception that was completely blocked by dihydro-β-erythroidine (DHβE; α4β2 antagonist) and partially blocked by methyllycaconitine (MLA; α7 antagonist). Epibatidine reversed heat hyperalgesia when microinjected in the RVM 4 h, 4 d, or 2 weeks after CFA treatment. Although DHβE completely blocked epibatidine's antihyperalgesic effect at 4 h, at 2 weeks it elicited only partial antagonism. Methyllycaconitine was ineffective at both time points. Epibatidine's 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 DHβE. Neither antagonist alone altered paw withdrawal latency in uninjured or CFA-treated rats, suggesting that neither α4β2 nor α7 nAChRs are tonically active in the RVM. TheBmaxandKdof α4β2 nAChRs in the RVM were unchanged after CFA treatment. These observations provide the first evidence of pharmacological plasticity of the actions of α4β2 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.
authors.affiliation: Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242; Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242.
authors.forename: Francis J
authors.identifier: 0000-0002-3129-1256
authors.initials: FJ
authors.lastname: Jareczek
authors.affiliation: Department of Anesthesia, University of Iowa , Iowa City, IA 52242.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: White
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242; Department of Anesthesia, University of Iowa, Iowa City, IA 52242; Department of Pharmacology, University of Iowa, Iowa City, IA 52242.
authors.forename: Donna L
authors.identifier: 0000-0002-2537-0441
authors.initials: DL
authors.lastname: Hammond
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018678:Cholinergic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D058748:Pain Perception / Q000187:drug effects / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D000700:Analgesics; D018678:Cholinergic Agents; D011978:Receptors, Nicotinic
keywords: antinociception; complete Freund’s adjuvant; epibatidine; nicotinic acetylcholine receptors; rostral ventromedial medulla