Activation of presynaptic NMDA receptors coupled to NaV1.8-resistant sodium channel C-fibers causes retrograde mechanical nociceptor sensitization.

The present study investigated whether activation of presynaptic N-methyl-d-aspartate (NMDA) receptors in the spinal cord produces a retrograde nociceptor sensitization (hypernociception) to mechanical nonnoxious stimulus. By using an electronic version of the von Frey hair test (pressure meter), s.c. intraplantar administration of prostaglandin E(2) (PGE(2)) (50-400 ng per paw) evoked a dose-related ipsilateral paw hypernociception. In contrast, intrathecal (i.t.) administration of NMDA (5-80 ng) and PGE(2) (15-150 ng) evoked dose-related bilateral paw hypernociception. The s.c. intraplantar administration of dipyrone (80-320 microg per paw) or morphine (3 and 9 microg per paw), usually used to antagonize peripheral PGE(2) (100 ng per paw), induced hypernociception and also antagonized the ipsilateral (without affecting the contralateral) paw hypernociception induced by i.t. injections of NMDA (40 ng) or PGE(2) (50 ng). These doses of drugs did not modify the basal mechanical sensitivity of control paws. This result shows that intraspinal NMDA or PGE(2) produces sensitization of the primary sensory neuron in response to mechanical stimulation. In a second series of experiments it was shown that the i.t. treatment with NaV1.8 (SNS/PN3) sodium channel antisense oligodeoxynucleotides, but not mismatch oligodeoxynucleotides, decreased the mRNA expression of sodium tetrodotoxin-resistant channels on the dorsal root ganglia and abolished the mechanical hypernociception induced by i.t. administration of NMDA. Thus, our results support the suggestion that glutamate release in the spinal cord during inflammation causes retrograde hypernociception of nociceptors associated with sodium tetrodotoxin-resistant channels in primary nociceptive sensory neurons.