Hyperalgesia induced by peripheral inflammation is mediated by protein kinase C betaII isozyme in the rat spinal cord.
We have addressed the molecular mechanism(s) of hyperalgesia, which depends on increased excitability of dorsal horn neurons and on sensitization of primary afferent nociceptors, during peripheral inflammation. Following unilateral adjuvant-induced inflammation in the rat hind paw, time-course changes in behavioral hyperalgesia and functional activities of Ca2+/phospholipid-dependent protein kinase C isozymes were examined. Inflammation was characterized by increase in paw diameter, and behavioral hyperalgesia was quantified as paw withdrawal latency from a radiant heat source. Behavioral hyperalgesia on the injected paw was significantly increased. This was accompanied by a significant increase in total functional membrane-associated protein kinase C activity, whereas total cytosolic protein kinase C activity was unchanged on the sides of the lumbar spinal cord both contralateral and ipsilateral to the inflammation. Importantly, on the side of lumbar cord ipsilateral to the inflamed paw, the activity of membrane-associated protein kinase CbetaII was increased following the same time-course as the paw withdrawal latency decrease, suggesting an increased translocation of protein kinase Cbetall to the membrane related to behavioral hyperalgesia. A defined mixture of purified gangliosides, which inhibits intracellular protein kinase C translocation and activation, decreased inflammation-induced paw withdrawal latency, and specifically decreased the activity of membrane-associated protein kinase Cbetall on the side of the spinal cord ipsilateral to the inflammation. Quantitative immunohistochemical analyses demonstrated intensified protein kinase CbetaII-like immunoreactivity on the side of the spinal cord ipsilateral to the inflammation. Time-course for increases in the activity of membrane-associated protein kinase CbetaII, and in intensity of protein kinase CbetaII-immunoreactivity, paralleled inflammation-mediated changes in paw withdrawal latency and paw diameter. Our findings indicate an apparent involvement of protein kinase CbetaII isozyme specifically in the molecular mechanism(s) of thermal hyperalgesia.
Igwe
O J
OJ
University of Missouri-Kansas City, School of Pharmacy, Division of Pharmacology, MO 64110, USA. igweo@umkc.edu
Chronwall
B M
BM
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005528:Foot / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D005620:Freund's Adjuvant / Q000494:pharmacology; D005732:Gangliosides / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009619:Nociceptors / Q000166:cytology / Q000201:enzymology; D010147:Pain Measurement / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
D005732:Gangliosides; D007527:Isoenzymes; D005620:Freund's Adjuvant; D011493:Protein Kinase C; D064546:Protein Kinase C beta