Sweet Relief: Behaviorally conditioned analgesia in rats with inflammatory pain

The sensation of pain is modulated by a variety of physiological and psychological factors resulting in nocebo hyperalgesia and placebo analgesia. Modern pain therapy is increasingly regarded as a multimodal approach that combines pharmacological and non-pharmacological interventions. Associative-learning paradigms offer a promising adjunctive strategy for improving pain relief. To elucidate the neurobiological underpinnings, translation into an animal model is therefore warranted. Here, we aimed to apply a taste-associative learning paradigm in a model of inflammatory pain to induce a state of conditioned analgesia in rats. Male Dark Agouti rats received an intraplantar injection of Complete Freund's adjuvant (CFA) to elicit inflammatory pain; ibuprofen (100 mg/kg) was used as analgesic. Pain-associated behavioral changes were assessed in an open field test, Von Frey test, and Plantar Heat test. For the conditioning experiments, treatment with ibuprofen as unconditioned stimulus (US) was paired to the presentation of a sweet taste of saccharin (conditioned stimulus; CS) on days 2, 4, and 6 after CFA-injection (acquisition). On day 8, conditioned responses were evoked by presenting saccharin followed by a placebo injection (retrieval). CFA induced clear behavioral adaptations, including reduced water intake, weight loss, diminished locomotor activity, and lower mechanical and thermal withdrawal thresholds. Spontaneous pain-associated behaviors returned to baseline from day 2 post-CFA, whereas stimulus-evoked behaviors remained attenuated throughout the experiment. Treatment with ibuprofen markedly raised withdrawal thresholds, confirming its analgesic effect. Pairing ibuprofen (US) with saccharin (CS) produced a conditioned taste avoidance (CTA). Rats that had undergone the conditioning displayed conditioned analgesia, evidenced by elevated thermal and mechanical withdrawal thresholds compared to the non-conditioned vehicle group. Our results demonstrate that a state of conditioned analgesia can be induced in rats using a taste-associative learning paradigm. Consequently, our model constitutes a valuable tool for further investigating the neurobiological mechanisms involved in placebo-mediated analgesia.