Learning pain in context: Response-conditioned placebo analgesia and nocebo hyperalgesia in male rats with chronic neuropathic pain

Abstract

BackgroundAnimal models of placebo analgesia and nocebo hyperalgesia have great potential to assist in the development of novel treatments for chronic pain that exploit or inhibit these phenomena. This study sought to elicit both conditioned placebo analgesia and conditioned nocebo hyperalgesia in rats with chronic neuropathic pain using non-pharmacological, contextual conditioning approaches, similar to those most often used in humans. MethodsSciatic nerve-injured male Sprague-Dawley rats (n = 80), and sham controls (n = 16), underwent a conditioning procedure in which three different thermal stimulus intensities (4 °C, 20 °C or 30 °C) were paired with contextual cues. Injured hind paw withdrawal behaviours were used to determine pain sensitivity, and either conditioned analgesia or conditioned hyperalgesia was evoked by re-exposing the rats to the same context with either an increased or decreased thermal stimulus, respectively. ResultsStronger conditioned analgesia and conditioned hyperalgesia were seen when rats were conditioned in a more complex environment, highlighting the importance of context in these processes. Rats that did not undergo conditioning procedures showed fewer hind paw withdrawals, indicating a learned component to these pain behaviours. ConclusionsOur data call attention to context and learning as two critical factors in the development of placebo and nocebo effects in male rodents with a neuropathic injury. Additionally, the response-conditioning model we present in this study affords better comparisons between human and animal studies, in particular for those seeking to identify commonalities in the neurobiological mechanisms of placebo and nocebo responses.