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 four hours, four days, or two weeks after CFA treatment. Although DHβE completely blocked epibatidine’s anti-hyperalgesic effect at four hours, at two 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 two weeks after CFA. Moreover, as early as four hours 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. The Bmax and Kd of 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.
Significance Statement: This article presents evidence that, over time, inflammatory injury diminishes the antinociceptive effects of an nAChR agonist in the brainstem and changes the receptors that mediate the agonist’s anti-hyperalgesic and antinociceptive effects. These data support the clinical hypothesis that those in chronic pain smoke more as a result of a decrease in the analgesic efficacy of nAChR activation.
- complete Freund’s adjuvant
- nicotinic acetylcholine receptors
- rostral ventromedial medulla
The authors declare no competing financial interests.
This work was supported by the National Institutes of Health National Institute of Drug Abuse [Grants R01 DA006736, F30 DA036964, T32 GM007337]