5-hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice

Opioid-induced hyperalgesia (OIH) and tolerance are challenging maladaptations associated with opioids in managing pain. Recent genetic studies and the existing literature suggest the 5-hydroxytryptamine type 3 (5-HT3) receptor participates in these phenomena. The location of the relevant receptor populations and the interactions between the 5-HT3 system and other systems controlling OIH and tolerance have not been explored, however. We hypothesized that 5-HT3 receptors modulate OIH and tolerance, and that this modulation involves the control of expression of multiple neurotransmitter and receptor systems. C57BL/6 mice were exposed to a standardized 4-day morphine administration protocol. The 5-HT3 antagonist ondansetron was administered either during or after the conclusion of morphine administration. Mechanical testing was used to quantify OIH, and thermal tail-flick responses were used to measure morphine tolerance. In other experiments spinal cord and dorsal root ganglion tissues were harvested for analysis of messenger RNA concentrations by real-time polymerase chain reaction or immunochemistry analysis. The results showed that (1) systemic or intrathecal injection of ondansetron significantly prevented and reversed OIH, but not local intraplantar injection; (2) systemic or intrathecal injection of ondansetron prevented and reversed tolerance; and (3) ondansetron blocked morphine-induced increases of multiple genes relevant to OIH and tolerance in dorsal root ganglion and spinal cord. Morphine acts via a 5-HT3-dependent mechanism to support multiple maladaptations to the chronic administration of morphine. Furthermore, the use of 5-HT3 receptor antagonists may provide a new avenue to prevent or reverse OIH and tolerance associated with chronic opioid use.