Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain.
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.
Gardell
L R
LR
Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Ibrahim
M
M
Wang
R
R
Wang
Z
Z
Ossipov
M H
MH
Malan
T P
TP
Porreca
F
F
Lai
J
J
D000818:Animals; D004399:Dynorphins / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D013045:Species Specificity; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D004399:Dynorphins; C087857:protein kinase C gamma; D011493:Protein Kinase C