MOUSE STRAINS THAT LACK SPINAL DYNORPHIN UPREGULATION AFTER PERIPHERAL NERVE INJURY DO NOT DEVELOP

Abstract—Several experimental models of peripheral neurop-athy 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 neu-ropathic pain after nerve injury, supporting a pronociceptive role of elevated levels of spinal dynorphin. A null mutation of the isoform of protein kinase C (PKC 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 PKC wild-type mice and the outbred mouse strain ICR, ligation of the L5 and L6 spinal nerves (SNL) elicited both tactile hypersensitivity and ther-mal 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 PKC KO mice and the 129S6 mice (which express PKC) did not show abnormal pain after SNL; neither strain showed elevated levels of spinal dynor-phin. The multiple phenotypic deficits in PKC KO mice con-found the interpretation of the proposed role of PKC-ex-pressing spinal neurons in neuropathic pain states. Addition-ally, the data show that the regulation of spinal dynorphin expression is a common critical feature of expression of neuropathic pain. © 2003 IBRO. Published by Elsevier Ltd. All rights reserved