Effects of xaliproden, a 5-HT1A agonist, on mechanical allodynia caused by chemotherapeutic agents in mice

In the present study we investigated whether xaliproden, a selective 5-HT1A receptor agonist, could relieve allodynia induced by three types of chemotherapeutic agents (paclitaxel, vincristine, and oxaliplatin) in mice. A single intraperitoneal injection of paclitaxel (5 mg/kg), vincristine (0.1 mg/kg), or oxaliplatin (3 mg/kg) time-dependently increased punctate stimulation-evoked allodynia over 10-14 days; the intensities of allodynia were similar between the treatment groups. A single oral dose of xaliproden (0.3-3 mg/kg) inhibited paclitaxel-induced allodynia in a dose-dependent manner. Xaliproden (3 mg/kg) administration produced a slight and no suppression of vincristine-induced and oxaliplatin-induced allodynia, respectively. The firing response of the tibial nerve to punctate stimulation increased in mice that received paclitaxel or oxaliplatin. Xaliproden (3 mg/kg) markedly inhibited the firing response in the mice treated with paclitaxel, while it partially inhibited the firing response in the oxaliplatin-treated animals. Vincristine did not significantly increase the tibial nerve response. Paclitaxel significantly increased the mRNA expression of 5-HT1A receptor in the dorsal root ganglia, but not in the spinal dorsal horn. In contrast, oxaliplatin significantly increased the mRNA expression of 5-HT1A receptor in the spinal dorsal horn, but not in the dorsal root ganglia. Vincristine did not affect the mRNA expression of 5-HT1A receptor in both these regions. These results suggest that xaliproden produces acute inhibition of mechanical allodynia induced by paclitaxel, but not by vincristine and oxaliplatin, via inhibition of the hyper-response of the primary afferent neurons.