Intrathecal CGRP8-37-induced bilateral increase in hindpaw withdrawal latency in rats with unilateral inflammation.
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.
Yu
L C
LC
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Hansson
P
P
Brodda-Jansen
G
G
Theodorsson
E
E
Lundeberg
T
T
D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D002351:Carrageenan; D004347:Drug Interactions; D006614:Hindlimb; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009292:Narcotic Antagonists; D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D009270:Naloxone; D002351:Carrageenan; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide