Intrathecal CGRP_8–37‐induced bilateral increase in hindpaw withdrawal latency in rats with unilateral inflammation

Abstract

1 Recent work in our laboratory has demonstrated that intrathecal administration of a selective antagonist of calcitonin gene-related peptide (CGRP), CGRP8-37, increased the hindpaw withdrawal latency (HWL) to thermal stimulation and hindpaw withdrawal threshold (HWT) to pressure in normal rats, and that these effects were more pronounced than in rats with mononeuropathy. 2 The present study was performed to investigate the effects of intrathecal administration of CGRP8-37 on the HWL and HWT in rats with unilateral hindpaw inflammation induced by subcutaneous injection of carrageenin. The effect of naloxone was also studied. 3 Subcutaneous injection of 0.1 ml of carrageenin into the plantar region of the left hindpaw induced a significant increase in the volume of the ipsilateral hindpaw (P <0.001), and significant bilateral decreases of the HWL to thermal stimulation (ipsilateral: P<0.001; contralateral: P<0.01) and HWT to pressure (ipsilateral: P<0.001; contralateral: P<0.01). 4 Intrathecal administration of 10 nmol of CGRP8 37, but not of 1 or 5 nmol, induced a significant bilateral increase in the HWL and HWT in rats with experimentally induced inflammation (thermal test: P<0.001; mechanical test: P<0.001). 5 The effect of intrathecal administration of 10 nmol CGRP8-37 on HWL and HWT was significantly more pronounced in intact rats than in rats with experimentally induced inflammation (ipsilateral: P<0.001; contralateral: P<0.001). 6 The effect of CGRP8 37 on withdrawal responses in the inflamed paw was partly reversed by intrathecal injection of naloxone at a dose of 88 nmol in the thermal (ipsilateral: P<0.01; contralateral: P=0.14) and mechanical tests (ipsilateral: P<0.05; contralateral: P=0.60). 7 A significant bilateral increase in the concentration of CGRP-like immunoreactivity in the perfusate of both hindpaws was demonstrated 24 h after unilateral injection of carrageenin (ipsilateral: P<0.001; contralateral: P<0.05). There was also an increase in the amount of CGRP-like immunoreactivity in the cerebrospinal fluid (P<0.001), but not in plasma (P=0.75). 8 The present study demonstrates that acute experimentally-induced unilateral hindpaw inflammation, induces bilateral increases in the amount of CGRP-like immunoreactivity in hindpaw perfusates. Intrathecal administration of CGRP8_37 increased the HWL to thermal stimulation and HWT to pressure bilaterally. 9 The results indicate that CGRP plays a role in the transmission of presumed nociceptive information in the spinal cord of rats with experimentally induced inflammation. Furthermore, our findings suggest that opioids can modulate CGRP-related effects in the spinal cord.

Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons

“…CGRP1 receptors are also important for spinal nociceptive transmission. Intrathecal or iontophoretic administration of a CGRP1 antagonist induced antinociception in normal naïve rats and in rats with hindpaw inflammation (Sun et al, 2003;Yu et al, 1994;Yu et al, 1996;Yu et al, 1998). CGRP8-37 also inhibited the responses of spinal dorsal horn neurons to transdermic electrical stimulation of the hindpaw (Yu et al, 1999) and to noxious mechanical stimulation of the knee joint (Neugebauer et al, 1996).…”

Ablation and Regeneration of Peripheral and Central TRPV1 Expressing Nerve Terminals and the Consequence of Nociception

“…Neuronal activity increases endovanilloid levels during chronic pain conditions, which are synthesized and released on demand [42][43][44][45][46]. Studies have shown that blocking neuropeptide release alleviates inflammatory [47][48][49] and neuropathic pain [50]. Drugs that inhibit activation of glia have been shown to alleviate chronic pain [51].…”

Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

“…It was reported that intrathecal administration of CGRP 8-37 induced very strong inhibition on the pain-related responses to thermal and mechanical noxious stimulations in rats, indicating that CGRP 8-37 induced strong analgesic effects in the spinal cord (45)(46)(47). The present study has shown that the CGRP antagonist is also effective against inflammatory pain in-…”

“…A number of similarities were identified between formalin-evoked pain and human persistent clinical inflammatory pain (44). The CGRP family peptides were shown to play important roles in inflammatory pain (14,20,27,45). In the chronic inflammatory pain models, both CGRP and its mRNA expression increased greatly in DRG neurons (13,27).…”