Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy-induced neuropathy: The role of spinal 5-HT3 receptors.

Chemotherapy-induced neuropathy (CIN) is a common complication of cancer treatment. Although CIN is treated with antidepressants that act at serotonin (5-HT) reuptake, the mechanisms of serotoninergic modulation of nociceptive transmission during CIN remain unknown, namely as to the involvement of the rostroventromedial medulla (RVM) and the role of spinal 5-HT3 receptors (5-HT3R). Male Wistar rats were injected with the cytostatic paclitaxel or vehicle solution. One month after CIN induction, we first studied the activation of RVM neurons, and then the activation of the local serotoninergic neurons. Immunostaining of phosphorylated extracellular signal-regulated kinase (pERK) indicated increased activation in paclitaxel-injected animals. The double immunohistochemistry of pERK and tryptophan hydroxylase (TpH) showed higher expression of TpH and increased co-localization of TpH and pERK of paclitaxel-injected animals, indicating that CIN is associated with increased activation of serotoninergic RVM neurons. The 5-HT content at the spinal dorsal horn assessed by HPLC was higher in paclitaxel-injected animals. The immunohistochemical analysis of 5-HT also showed increased expression at the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The levels of 5-HT3R detected by immunohistochemistry were higher in the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The intrathecal administration of the 5-HT3R antagonist ondansetron reversed mechanical and cold hypersensitivity in the von Frey and cold plate tests, respectively. The results indicate that CIN is associated with increased recruitment of descending 5-HT-mediated modulation from the RVM which affects the spinal serotoninergic system and probably accounts for pain hypersensitivity due to the pronociceptive role of spinal 5-HT3R.