Treatment with ketanserin produces opioid-mediated hypoalgesia in the late phase of carrageenan-induced inflammatory hyperalgesia in rats

Abstract

Both pro-nociceptive and antinociceptive mediators are released in the tissues during inflammation. Balance of these two types of mediators determines the induction and maintenance of pain or hypernociception. This study was designed to explore whether 5-HT2A receptors in the periphery contributed to the maintenance of carrageenan-evoked hyperalgesia. Intraplantar (i.pl.) injection of carrageenan evoked hyperalgesia detected by noxious heat stimulus. The 5-HT2A receptor antagonist ketanserin administered i.pl. 1 h after carrageenan dose-dependently (2–20 μg) prolonged paw withdrawal latency (PWL) during the late phase (24 h) of carrageenan-evoked inflammation. Following treatments with carrageenan and ketanserin, i.pl. injection of formalin (1%) produced significantly fewer nocifensive behaviors and expression of c-Fos protein in the spinal dorsal horn, confirming the hypoalgesic status in the inflamed site. However, injection of ketanserin in naive site failed to produce hypoalgesia. The hypoalgesia was completely abolished by local or systemic injection of naloxone methiodide. The present study suggests that 5-HT2A receptors were involved in the maintenance of inflammatory pain, and that 5-HT suppressed inflammation-associated endogenous opioid analgesia contributing to its pro-nociceptive actions in the periphery. It implied a possible therapeutic benefit of blockade of local 5-HT2A receptors in the treatment of inflammatory pain.