Role of peripheral and spinal 5-HT3 receptors in development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia

Abstract

The role of peripheral and spinal 5-HT3 receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In experiments where the test drug was anticipated to augment or antagonize the response, 0.5 or 1% formalin, respectively, was used for injection. Peripheral ipsilateral, but not contralateral, pre-treatment (−10min) with serotonin (5-HT, 10–100nmol/paw) and the selective 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (m-CPBG, 10–300nmol/paw) increased 0.5% formalin-induced secondary allodynia and hyperalgesia in both paws. Moreover, spinal pre-treatment with m-CPBG (10–300nmol/rat) increased 0.5% formalin-induced secondary hyperalgesia but not allodynia in both paws. Accordingly, peripheral ipsilateral (30–300nmol/paw), but not contralateral (300nmol/paw), and spinal (10–100nmol) pre-treatment with the selective 5-HT3 receptor antagonist ondansetron prevented 1% formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. The peripheral pronociceptive effects of 5-HT (100nmol/paw) and m-CPBG (300nmol/paw) as well as the spinal effect of m-CPBG (300nmol/rat) were completely prevented by the peripheral (10nmol/paw) and spinal (1nmol/rat) injection, respectively, of ondansetron. At these doses, ondansetron did not modify per se formalin-induced nociceptive behaviors. Spinal (30–300nmol/rat), but not peripheral (300nmol/paw), post-treatment (on day 6) with ondansetron reversed established formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT3 receptors participates in the development of formalin-induced long-term secondary allodynia and hyperalgesia in the rat. In addition, our data suggest that spinal 5-HT3 receptors play an important role during development and maintenance of these evoked long-term behaviors.