A new experimental rat model of nocebo‐related nausea involving double mechanisms of observational learning and conditioning

Abstract

AimThe nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo‐related nausea by combining observational learning and Pavlovian conditioning paradigms.MethodsMale Sprague–Dawley rats with nitroglycerin‐induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms.ResultsBoth strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5‐hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c‐Fos‐positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus‐dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days.ConclusionThe present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.