Glucocorticoid Inhibition of Neuropathic Hyperalgesia and Spinal Fos Expression

Wade S. Kingery, Geeta S. Agashe, Shigehito Sawamura, M. Frances Davies, J. David Clark, Mervyn Maze
2001 Anesthesia and Analgesia  
Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were
more » ... ucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK 1 receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK 1 immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids. (Anesth Analg 2001;92:476 -82) C omplex regional pain syndrome type II (CRPS II or causalgia) has been defined as a syndrome that starts after a nerve injury and is not necessarily limited to the distribution of the injured nerve. The diagnosis requires pain, allodynia, or hyperalgesia disproportionate to injury; evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain; and no other conditions that would otherwise account for the degree of pain and dysfunction (1). There is no consensus on the pathophysiology of this condition and whether any treatment for CRPS is effective; hence, current therapeutic management tends to adopt a trial-and-error approach (2). Two small randomized controlled trials have reported that a 4 -12-wk course of large-dose glucocorticoids, administered orally three or four times daily, can alleviate pain, hyperalgesia, and edema in CRPS patients (3,4). Interestingly, this effect can be curative, frequently persisting after the medication is discontinued (3,5). Despite these promising clinical findings, glucocorticoids are rarely used as a first-line treatment for CRPS in pain clinics, and there are no data regarding the mechanisms of action or physiologic responses to glucocorticoids in a CRPS model. Previously we demonstrated that sciatic nerve transection in rats caused the gradual development of spontaneous pain behavior (autotomy), limb edema, and the development of hyperalgesia in a territory outside that of the injured nerve, a syndrome resembling CRPS (6). With this model, we examined the effects of once-daily methylprednisolone injections (3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 for 21 days); this regimen was predicated by pharmacodynamic data derived from surrogate effect marker studies. Although this methylprednisolone regimen prevented the development of autotomy pain behavior and hindpaw edema, it had no effect on heat or mechanical hyperalgesia (6).
doi:10.1097/00000539-200102000-00037 pmid:11159254 fatcat:aiuu4rrqcrentljbv2kbade2um