The spontaneous hyperalgesia observed in humans and mice after chronic exposure to opioids, which is referred to as OIH [34], is another measure of physical dependence [35-37]. In our experiments, chronic morphine treatment caused hyperalgesia in C57BL/6J mice. We chose to measure sensitization to a mechanical stimulus as this provides a robust degree of sensitization [14]. Ondansetron administration had no effect on pain sensitivity in control mice that were not treated with morphine, but reversed the hyperalgesia that developed during morphine abstinence (Fig. 4). Taken together, these experiments show that a 5-HT3 receptor antagonist markedly reduced the severity of two distinct measures of physical dependence on morphine.
