Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity

Peripheral inflammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. Infl ammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin ge ne-related peptide (CGRP). In the present study, mice deficient in the calc itonin/alpha CGRP gene (CGRP(-/-)) displayed normal responses to noxious st imuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint inflammation in two t ests that assess central sensitization, through testing at sites remote fro m the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP( - /-) mice showed no signs of secondary hyperalg esia after development of knee joint inflammation, while the expected signi ficant decrease in the PWL was observed in the CGRP(+/+) mice as control. T he CGRP(-/-) mice also had a prolonged rather than a shortened response lat ency in the hot-plate test 4 h after knee joint injection of k/c. Immunohis tological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(-/-) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral inflammatory events including the development of nociceptive behaviors. (C) 2001 Intern ational Association for the Study of Pain. Published by Elsevier Science B. V. All rights reserved.