Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat.
1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.
Ahlgren
S C
SC
Department of Anatomy, University of California, San Francisco 94143-0452A.
Levine
J D
JD
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D019311:Staurosporine; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D000470:Alkaloids; D010446:Peptide Fragments; C072093:protein kinase C (19-36); D011493:Protein Kinase C; D019311:Staurosporine