Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization.
Calcitonin gene-related peptide (CGRP), acting through CGRP receptors, produces behavioral signs of mechanical hyperalgesia in rats and sensitization of wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Although involvement of CGRP receptors in central sensitization has been confirmed, the second-messenger systems activated by CGRP receptor stimulation and involved in pain transmission are not clear. This study tested whether the hyperalgesia and sensitizing effects of CGRP receptor activation on WDR neurons are mediated by protein kinase A or C (PKA or PKC) signaling. Intrathecal injection of CGRP in rats produced mechanical hyperalgesia, as shown by paw withdrawal threshold tests. CGRP-induced hyperalgesia was attenuated significantly by the CGRP1 receptor antagonist, CGRP8-37. The effect was also attenuated significantly by a PKA inhibitor (H89) or a PKC inhibitor (chelerythrine chloride). Electrophysiological experiments demonstrated that superfusion of the spinal cord with CGRP-induced sensitization of spinal dorsal horn neurons. The CGRP effect could be blocked by CGRP8-37. Either a PKA or PKC inhibitor (H89 or chelerythrine) also attenuated this effect of CGRP. These results are consistent with the hypothesis that CGRP produces hyperalgesia by a direct action on CGRP1 receptors in the spinal cord dorsal horn and suggest that the effects of CGRP are mediated by both PKA and PKC second-messenger pathways.
Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, 301 University Blvd., Galveston, Texas 77555-1069, USA.
Rui-Qing
RQ
Sun
Yi-Jun
YJ
Tu
Nada B
NB
Lawand
Jing-Yin
JY
Yan
Qing
Q
Lin
William D
WD
Willis
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004594:Electrophysiology / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000503:physiopathology*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
D007546:Isoquinolines; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide