Peripheral norepinephrine exacerbates neuritis-induced hyperalgesia.

Inflammation of a peripheral nerve (neuritis) causes mechanical and thermal hyperalgesia in the region in which the inflamed nerve innervates. We investigated whether peripherally applied norepinephrine (NE) would exacerbate mechanical hyperalgesia in rats with neuritis. After inflammation of the left L5 spinal nerve with complete Freund's adjuvant, the foot withdrawal thresholds to mechanical stimuli applied to the affected hind paw (mechanical thresholds) were decreased significantly, indicating the development of mechanical hyperalgesia. An intradermal injection of NE to the affected paw further aggravated mechanical hyperalgesia transiently (1-3 days) and then recovered to the pre-NE injection levels afterwards. This responsiveness to NE (adrenergic sensitivity) was observed not only while rats were showing inflammatory hyperalgesia but also after recovering from it. The effect of NE on mechanical hyperalgesia was mediated by both peripheral alpha(1)- and alpha(2)-adrenoceptors. Immunohistochemical study of the previously inflamed nerve showed that proinflammatory cytokine tumor necrosis factor immunoreactivity was significantly higher in the rats showing adrenergic sensitivity compared to rats without adrenergic sensitivity. The data thus suggest that peripheral NE, when released in an excessive amount from the sympathetic nervous system, might play an important role in the aggravation of pain in neuritis.