Several experimental models of
peripheral neuropathy show that a significant upregulation of spinal
dynorphin A and its precursor
peptide,
prodynorphin, is a common consequence of nerve injury. A genetically modified mouse strain lacking
prodynorphin does not exhibit sustained
neuropathic pain after nerve injury, supporting a pronociceptive role of elevated levels of spinal
dynorphin. A null mutation of the gamma
isoform of
protein kinase C (PKCgamma KO [knockout]), as well as an inbred mouse strain, 129S6, also does not manifest behavioral signs of
neuropathic pain following
peripheral nerve injury. The objective of this study was to extend our observations to these genetic models to test the hypothesis that elevated levels of spinal
dynorphin are essential for the maintenance of abnormal
pain. In PKCgamma wild-type mice and the outbred mouse strain ICR,
ligation of the L5 and L6 spinal nerves (SNL) elicited both tactile
hypersensitivity and
thermal hyperalgesia. Both strains showed a significant elevation in
dynorphin in the lumbar spinal dorsal horn following SNL. Spinal administration of an anti-
dynorphin A antiserum blocked the thermal and tactile
hypersensitivity in both strains of mice. However, the PKCgamma KO mice and the 129S6 mice (which express PKCgamma) did not show abnormal
pain after SNL; neither strain showed elevated levels of spinal
dynorphin. The multiple phenotypic deficits in PKCgamma KO mice confound the interpretation of the proposed role of PKCgamma-expressing spinal neurons in
neuropathic pain states. Additionally, the data show that the regulation of spinal
dynorphin expression is a common critical feature of expression of
neuropathic pain.