The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C.
This series of studies has investigated the involvement of the NMDA receptor and the translocation of PKC in the seemingly unrelated phenomena of neuropathic pain and tolerance and dependence to narcotic analgesic drugs. This work has demonstrated that the NMDA receptor and PKC translocation are importantly involved in neuropathic pain and morphine tolerance or dependence and that these phenomena may be importantly interrelated. Neuropathic pain following nerve injury is a major chronic pain syndrome. Utilizing a rat model of painful peripheral mononeuropathy produced by CCI of the sciatic nerve, the authors have investigated central mechanisms of postinjury neuropathic pain. Behavioral and pharmacological studies indicate that thermal hyperalgesia and spontaneous pain behaviors observed in this model are attenuated by treatment with NMDA receptor antagonists. A consequence of NMDA receptor activation is calcium influx, which in turn can result in translocation of PKC from cytosol to membrane. Inhibitors of intracellular PKC translocation and activation block thermal hyperalgesia and spontaneous pain behaviors after CCI and also reduce the elevated spinal cord neural activity in CCI rats. Furthermore, spinal cord levels of membrane-bound PKC reliably increase in CCI rats as a result of translocation of PKC revealed by the [3H]PDBu autoradiographic assay. This increase in membrane-bound PKC is associated with postinjury neuropathic pain behaviors in CCI rats and both pain-related behaviors and membrane-bound PKC are reduced potently by GM1 ganglioside.
Mayer
D J
DJ
Department of Anesthesiology, Virginia Commonwealth University, Richmond 23298, USA.
Mao
J
J
Price
D D
DD
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004361:Drug Tolerance; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D010146:Pain / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D011493:Protein Kinase C / Q000378:metabolism*
D009020:Morphine; D011493:Protein Kinase C