Effects of calcitonin gene-related peptide-(8-37) on withdrawal responses in rats with inflammation

Abstract

The present study was performed to explore the effect of subcutaneous injection of carrageenan into the rat plantar region on hindpaw edema formation and the latency of hindpaw withdrawal to presumed nociceptive stimulation. Subcutaneous injection of carrageenan into the left hindpaw induced a significant increase in the volume of the left hindpaw, leaving the right side unaffected. In addition, we found a bilateral decrease in hindpaw withdrawal latency to heat and mechanical, but not to cold stimulation. The decreased bilateral hindpaw withdrawal latency to heat stimulation lasted for 14 days after carrageenan injection. The decreased bilateral hindpaw withdrawal latency to mechanical stimulation lasted for 2 days after the injection, then reversed and increased from day 3 to 14. Intrathecal injection of either 10 nmol of calcitonin gene-related peptide 8-37 or 26.6 nmol of morphine induced significant bilateral increases in hindpaw withdrawal latency, which were more pronounced with the morphine. The results show that experimentally induced unilateral hindpaw inflammation induces a bilateral decrease in hindpaw withdrawal latencies to presumed nociceptive stimulation while the sensory systems for heat and mechanical stimulation were differently affected after carrageenan injection.

Introduction

It has been Suggested that primary sensory neurons play a dual role in the response to acute injury, where the central terminals transmit information set up by the noxious event to the central nervous system, and the peripheral terminals mediate a local inflammatory response via the axon reflex (Mayer et al., 1988). Sluka et al. (1995)have suggested that dorsal root reflexes also play an important role in the local inflammatory response. It has been reported that experimentally induced acute inflammation results in an enhanced release of the neuropeptide calcitonin gene-related peptide (CGRP) into peripheral tissues and cerebrospinal fluid (Bileviciute et al., 1993, Bileviciute et al., 1994). In the periphery CGRP has been shown to potentiate edema formation (Brain and Williams, 1985, Brain and Williams, 1989) and in the spinal cord CGRP has been shown to be involved in the transmission of presumed nociceptive information (Biella et al., 1991; Kawamura et al., 1989; Satoh et al., 1992; Yu et al., 1994Yu et al., 1995Yu et al., 1996aYu et al., 1996b). Recently, Neugebauer et al. (1996)reported that CGRP is involved in the spinal processing of mechanosensory input and in the generation and maintenance of hyperexcitability of dorsal horn neurons during the development of acute inflammation. A role for CGRP in nociception is also supported by studies reporting that intrathecal administration of a CGRP receptor antagonist, CGRP-(8-37), induced an increase in hindpaw withdrawal latency in rats with acute inflammation (Yu et al., 1996a).

Carrageenan induced inflammation is a commonly used model for the study of edema formation and nociception (Lundeberg et al., 1993; Mayer et al., 1988; Millan et al., 1988; Satoh et al., 1992; Vinegar et al., 1969; Winter et al., 1962). In the present study we set out to further previous observations in our laboratory by investigating changes in hindpaw withdrawal latencies to nociceptive mechanical, heat and cold stimulation in the carrageenan model. To our knowledge the response to cold stimulation has not been evaluated in studies on chronic inflammation induced by carrageenan. Previously, the carrageenan model has generally been used to investigate short term changes. In the present study the temporal pattern of hindpaw withdrawal latencies was investigated for a period of 2 weeks. As the primary sensory neurons may contribute to the local inflammatory process edema formation was also assessed. Both pro- and antinociceptive effects of intrathecal administration of the CGRP receptor antagonist CGRP-(8-37) (Chiba et al., 1989) have been reported (Neugebauer et al., 1996; Xu and Wiesenfeld-Hallin, 1996; Yu et al., 1994), therefore, the effects of GRP-(8-37) were again assessed and compared with morphine.