Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment

The specific mechanisms by which nervous system injury becomes a chronic pa in state remain undetermined. Historically, it has been believed that injur ies proximal or distal to the dorsal root ganglion (DRG) produce distinct p athologies that manifest in different severity of symptoms. This study inve stigated the role of injury site relative to the DRG in (1) eliciting behav ioral responses, (2) inducing spinal neuroimmune activation, and (3) respon ding to pharmacologic interventions. Rats received either an L5 spinal nerv e transection distal to the DRG or an L5 nerve root injury proximal to the DRG. Comparative studies assessed behavioral nociceptive responses, spinal cytokine mRNA and protein expression, and glial activation after injury. In separate studies, intrathecal pharmacologic interventions by using selecti ve cytokine antagonists (interleukin-1 [IL-1] receptor antagonist and solub le tumor necrosis factor [TNF] receptor) and a global immunosuppressant (le flunomide) were performed to determine their relative effectiveness in thes e injury paradigms. Behavioral responses assessed by mechanical allodynia a nd thermal hyperalgesia were almost identical in the two models of persiste nt pain, suggesting that behavioral testing may not be a sensitive measure of injury. Spinal IL-1 beta, IL-6, IL-10, and TNF mRNA and IL-6 protein wer e significantly elevated in both injuries. The overall magnitude of express ion and temporal patterns were similar in both models of injury. The degree of microglial and astrocytic activation in the L5 spinal cord was also sim ilar for both injuries. In contrast, the pharmacologic treatments were more effective in alleviating mechanical allodynia for peripheral nerve injury than nerve root injury, suggesting that nerve root injury elicits a more ro bust, centrally mediated response than peripheral nerve injury. Overall, th ese data implicate alternate nociceptive mechanisms in these anatomically d ifferent injuries that are not distinguished by behavioral testing or the n euroimmune markers used in this study. (C) 2001 Wiley-Liss, Inc.