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Keywords:

  • chronic pain;
  • inflammatory hyperalgesia;
  • protein kinase c-epsilon;
  • sensory neuron;
  • tumor necrosis factor-α

Abstract

Carrageenan-induced inflammatory pain lasting hours to days produces a protein kinase C epsilon (PKCɛ)-dependent ‘primed’ state lasting several weeks, during which time injection of prostaglandin E2 induces hyperalgesia which is markedly enhanced and prolonged compared to PGE2-induced hyperalgesia in normal ‘unprimed’ rats. In the present study, we demonstrate that while inhibition of prostaglandin synthesis and antagonism of β2-adrenergic receptors markedly attenuated the hyperalgesia induced by carrageenan, these interventions did not affect hyperalgesic priming. Tumor necrosis factor-α (rat recombinant; rrTNFα), another mediator of carrageenan-induced inflammation, alone produced hyperalgesia and priming, which were attenuated and prevented, respectively, by intrathecal administration of antisense to PKCɛ. Inhibition of TNFα with thalidomide or a rat polyclonal anti-TNFα antibody attenuated carrageenan-induced hyperalgesia and prevented priming. Intrathecal administration of antisense to tumour necrosis factor receptor type-1 (TNFR1) reduced the level of TNFR1 transported toward the peripheral terminals of sensory neurons, and attenuated both carrageenan- and rrTNFα-induced priming. Acute hyperalgesia induced by carrageenan or rrTNFα remained intact in animals treated with TNFR1 antisense. Our results demonstrate that the generation of the primed state does not require production of hyperalgesia and that TNFα, which is generated during acute inflammation, can act on sensory neurons to induce hyperalgesic priming by activating neuronal PKCɛ.