A chronic constriction injury to the sciatic nerve of the rat produces a painful peripheral neuropathy that is very similar to the neuropathic pain states seen in man. In the peripheral nervous system, light- and electron-microscopy showed that within 8 days the injury results in a partial and differential deafferentation that interrupts nearly all of the myelinated axons but spares a large majority of the small unmyelinated axons. The neuropathy has been found to produce a near total depletion of norepinephrine, in the axons that comprise the sympathetic perivascular plexus. The time course of this depletion has been shown to parallel the time course of the rats' temperature abnormality. The temperature abnormality has been confirmed with infrared thermography. A time course study shows that the temperature abnormality has a temporal evolution that resembles that seen in humans with causalgia/RSD. Specifically, the affected hindpaw is initially hot and then progresses to a chronic cold status. We have documented a substantial amount of short-term (hours to days) variability in the temperature abnormality. It is a common clinical assumption that the temperature abnormality seen in causalgia/RSD is due to abnormal sympathetic discharge. However, this assumption may often be incorrect. Many animals with an affected extremity that is abnormally cold have no NE-positive axons on their vasculature, and thus the cold skin cannot be due to excessive vasoconstrictor discharge. The hindpaw temperature abnormality has a paradoxical response to alpha2-adrenoceptor blockers. Instead of the normal warming, the affected hindpaw becomes cold. Previous work has shown that the neuropathy evokes a large increase in the level of the opioid peptide, dynorphin A1-8, but not in the level of enkephalin, in lumbar dorsal horn neurons. Measurement of mRNA levels have now shown that there is a corresponding up-regulation of the dynorphin gene but not of the enkephalin gene. The experimental neuropathy evokes marked changes in the levels of receptor binding for opioid ligands. At 2 days post-injury, there is an increase in binding in the superficial laminae of the dorsal horn for the mu, delta, and kappa sites. At 10 days, there is a decrease of mu binding in lamina V, a decrease in delta binding in laminae I-II, and also a decrease in kappa binding in laminae V and X. These data suggest that the neuropathic pain state may activate endogenous pain modulating circuitry, and also suggest that neuropathic pain patients may have an altered response to narcotic analgesics.
