People whose peripheral nerves have been damaged by trauma or disease sometimes develop chronic pain syndromes that are difficult or impossible to treat. This project investigates this problem with the aide of an experimentally-induced painful peripheral neuropathy in rats that is created by tying loosely constrictive ligatures around the sciatic nerve (the CCI model) or around a branch of the trigeminal nerve, the infraorbital nerve (the PTN model). The animals have abnormal pain sensations like those seen in humans. In particular, they have hyperalgesia (exaggerated responses to painful stimulation) to thermal and mechanical stimuli, allodynia (pain from normally innocuous stimuli) to touch, and spontaneous pain (or dysesthesia). A recently introduced anti- epileptic drug, felbamate, was found to suppress hyperalgesia and allodynia in the CCI model, without having any effect on the pain responses of normal rats. The anti-hyperalgesic and anti-allodynic effects were obtained with systemic doses that did not produce side- effects. Recent clinical reports indicate that felbamate has an unacceptable safety profile. Nevertheless these results suggest that a drug cocktail mimicking felbamate's mechanisms of action may be useful. Another recently introduced anti-epileptic, gabapentin, was shown in the CCI model to suppress heat-hyperalgesia and mechano- allodynia, but not mechano-hyperalgesia, at doses that did not produce side-effects. Comparable effects were obtained when the drug was administered intrathecally, suggesting that the mechanism of action is at the level of the spinal cord. Interruption of the efferent sympathetic innervation of the painful body region is known to eliminate or reduce neuropathic pain in some patients. Previous studies, however, have shown that sympatholysis has little or no effect in CCI rats. In contrast, we have recently shown that sympatholysis (stellate ganglionectomy) blocks heat- hyperalgesia in PTN rats. These results indicate that comparable injuries to different nerves may produce pain syndromes with fundamentally different underlying mechanisms.
