The effect of phorbol esters on spinal cord amino acid concentrations and responsiveness of rats to mechanical and thermal stimuli

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There is now mounting evidence supporting the hypothesis that pathological perceptual disorders described as secondary hyperalgesia and allodynia may be due to sensitization of spinal cord dorsal horn neurons. Protein kinase C (PKC) is thought to be one of the factors in the cascade of events leading from peripheral tissue damage to the sensitization of central neurons. In our experiments, we have used local microdialysis administration of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to activate PKC in the spinal cord dorsal horn in awake rats. In behavioral tests the responsiveness of the animals to von Frey filaments (1–1200 mN) and to heat stimuli applied to the hindpaws was tested. Thirty minutes after the TPA infusion the threshold for the paw withdrawal response was significantly decreased (from 160 to 6 mN) and the responses to suprathreshold stimuli were more robust. An increased mechanical sensitivity was no longer present when tested 1.5 and 5 h after the TPA application was terminated. When heat stimuli were tested, the TPA infusion resulted in a significantly prolonged time during which the animals held their hindpaws above the supporting surface after the heat stimulus (0.5 and 1.5 h after TPA), and in a decreased threshold for the heat stimulus (latency of withdrawal) 5 h after TPA. HPLC analysis of the perfusate obtained by microdialysis in vivo showed a significant increase in the extracellular levels of aspartate, glutamate, glycine and taurine, and a decrease of the glutamine level during TPA infusion. The levels of asparagine, serine, threonine and alanine did not change. Application of the inactive phorbol ester (α-TPA) did not evoke any change from the control values either in the AA concentrations or in the behavioral tests. Our results suggest that activation of PKC in the spinal cord evokes mechanical allodynia and thermal hyperalgesia and provides further evidence that PKC is involved in the process of the modulation of nociceptive information at the spinal cord level.

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