Hyperalgesic priming is restricted to isolectin B4-positive nociceptors

We have previously described a rat model for the contribution of neuroplastic changes in nociceptors to the transition from acute to chronic pain. In this model a prior injury activates protein kinase C epsilon (PKCε), inducing a chronic state characterized by marked prolongation of the hyperalgesia induced by inflammatory cytokines, prototypically prostaglandin E2 (PGE2), referred to as hyperalgesic priming. In this study we evaluated the population of nociceptors involved in priming, by lesioning isolectin B4-positive (IB4(+)) nociceptors with intrathecal administration of a selective neurotoxin, IB4-saporin. To confirm that the remaining, TrkA(+)/IB4(−), nociceptors are still functional, we evaluated if nerve growth factor (NGF) induced hyperalgesia. While pretreatment with IB4-saporin eliminated the acute mechanical hyperalgesia induced by glia-derived neurotrophic factor (GDNF), NGF and ΨεRACK, a highly selective activator of PKCε, induced robust hyperalgesia. After injection of NGF, GDNF or ΨεRACK, at a time at which hyperalgesia induced by PGE2 is markedly prolonged (hyperalgesic priming) in control rats, in IB4-saporin-pretreated rats PGE2 failed to produce this prolonged hyperalgesia. Thus, while PKCε is present in most dorsal root ganglion neurons, where it can contribute to acute mechanical hyperalgesia, priming is restricted to IB4(+)-nociceptors, including those that are TrkA(+). While PKCε activation can induce acute hyperalgesia in the IB4(+) population, it fails to induce priming. We suggest that hyperalgesic priming occurs only in IB4(+) nociceptors, and that in the peripheral terminals of nociceptors separate intracellular pools of PKCε mediate nociceptor sensitization and the induction of hyperalgesic priming.