Role of peripheral versus spinal 5‐HT 7 receptors in the modulation of pain undersensitizing conditions

Several studies have suggested that 5‐HT 7 receptors are involved in nociceptive processing but the exact contribution of peripheral versus central 5‐HT 7 receptors still needs to be elucidated. In the present study, the respective roles of peripheral and spinal 5‐HT 7 receptors in the modulation of mechanical hypersensitivity were investigated under two different experimental pain conditions. In a first set of experiments, the selective 5‐HT 7 receptor agonist, E ‐57431, was systemically, intrathecally or peripherally (intraplantarly) administered to rats sensitized by intraplantar injection of capsaicin. Oral administration of E ‐57431 (1.25–10 mg/kg) was found to exert a clear‐cut dose‐dependent reduction of capsaicin‐induced mechanical hypersensitivity. Interestingly, intrathecal administration of E ‐57431 (100  μg ) also inhibited mechanical hypersensitivity secondary to capsaicin injection. In contrast, a dose‐dependent enhancement of capsaicin‐induced mechanical hypersensitivity was observed after local intraplantar injection of E ‐57431 (0.01–1  μg ). In a second set of experiments, E ‐57431 was systemically or intrathecally administered to rats submitted to neuropathic pain (spared nerve injury model). Significant inhibition of nerve injury‐induced mechanical hypersensitivity was found after intraperitoneal (10  mg/kg ) as well as intrathecal (100  μg ) administration of E ‐57431 in this chronic pain model. These studies provide evidence that, under sensitizing neurogenic/neuropathic conditions, activation of 5‐HT 7 receptors exerts antinociceptive effects at the level of the spinal cord and pronociceptive effects at the periphery. The antinociceptive effect mediated by central 5‐HT 7 receptors seems to predominate over the pronociceptive effect at the periphery when a selective 5‐HT 7 receptor agonist is systemically administered.