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.