Peripheral and spinal mechanisms of neuropathic pain in the rat

The Chung peripheral nerve injury model shows consistent allodynia and thermal hyperalgesia, which represent the most common clinical neuropathic pain symptoms. Also clinically relevant, in the Chung model spinal morphine was inactive against tactile allodynia and diminished in potency in acute nociception without spinal/supraspinal antinociceptive synergy. Further, there are increased levels of dynorphin in multiple segmental regions of the spinal cord. This loss of spinal/supraspinal synergy and the spinal antiallodynic effect of morphine is restored by spinal MK-801 or antiserum to dynorphin.;It is shown here that spinal transection blocks tactile allodynia, but not thermal hyperalgesia in Chung model rats, suggesting that thermal hyperalgesia involves both spinal and supraspinal circuits, whereas tactile allodynia depends on a supraspinal loop.;The c-fiber specific neurotoxin resiniferatoxin before or after Chung surgery abolishes thermal nociception in Chung and sham-operated rats, but not allodynia in Chung model rats. These data suggest that tactile allodynia may be mediated by Abeta-fibers rather than c-fibers, offering a mechanistic basis for the observed insensitivity of allodynia to spinal morphine in Chung model rats.;The data also show that PN3 sodium channel protein expression is increased in medium to large diameter neurons in the L4 ipsilateral DRG of Chung rats, and that selective knockdown of PN3 protein in the DRG with specific antisense prevents and reverses allodynia and hyperalgesia in Chung model rats without affecting normal nociceptive functions. Meanwhile, the increased dynorphin level in the spinal cord of Chung model rats returns to normal following spinal PN3 antisense. This suggests that increased PN3 protein in the DRG of Chung model rats may underlie an important mechanism for central sensitization and peripheral ectopic firing after nerve injury. Increased expression of PN3 is also found in the DRGs of diabetic and CFA model rats; knockdown of PN3 reverses allodynia and thermal hyperalgesia in these models.;Together, these data suggest that relief from peripheral nerve injury, chronic inflammation, or diabetic neuropathy might be achieved by selective blockade of PN3. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.