Bilateral neurogenic mechanisms following acute unilateral inflammation

Abstract: The contribution of neurogenic mechanisms to inflammation has been extensively studied during the last decade, but provides no clear understanding of the bilateral changes commonly seen following unilateral stimulation. This work demonstrates that bilateral neurogenic mechanisms are a part of general host defence reactions following acute unilateral challenge, for the first time revealing that local anaesthetics applied contralaterally, might be used for therapeutic purposes i n relieving pain and inflammation. Unilateral injection of a pro-inflammatory substance (50µg of Freund's adjuvant, 50µl of 2% carrageenan, 50µg IL-1[alpha] or 50µl of 10-5 M of substance P) into a rat's knee induced a bilateral release of substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) as compared to saline injection. No visual signs of inflammation are found in the non-injected knee. The same injection with pro- inflammatory substance also induced significant changes in neuropeptide-LI in cerebrospinal fluid (CSF) and plasma, indicating a general activation of the nervous system following an acute challenge. Intraperitoneal injection of 50µg of IL-1[alpha] or subcutaneous injection of 50µg of Freund's adjuvant increased CGRP-LI in CSF, in plasma and the knee joint perfusate bilaterally, while concentrations of SP- , NKA- and NPY-LI were either decreased/ increased or unchanged. Taken together, the general release of neuropeptide-LI following acute challenge may be considered a part of a general host defence reaction. To investigate further the neurogenic mechanisms involved in bilateral responses, CGRP 300 pmol was injected into the rat hindpaw. Unilateral injection of CGRP 300 pmol induces a bilateral edema formation lasting for 24h and the release of CGRP-LI on the contralateral side, the latter abolished by common sciatic nerve section. Edema formation is attenuated by injection of CGRP 300 pmol concomitantly with the antagonist to CGRP-, 5-HT2- or 5-HT3-receptors, indicating that the mast cell mechanisms are involved. Bilateral edema formation is also abolished b y intrathecal pretreatment with bicuculline, the GABAA-receptor antagonist, supporting the involvement of dorsal root reflexes. However, ipsilateral but not contralateral edema formation is also reduced by intrathecal pretreatment with the CGRP antagonist, CGRP8-37, and saline, indicating that block or dilution of neurogenic substances at the spinal cord level prevents the bilateral interaction of what might be termed cross-spinal reflexes. The existence of such reflexes is further supported by demonstrating that contralateral pretreatment with local anaesthetics (xylocain or bupivacaine) for 24h inhibited, in a dose dependent manner, the bilateral decrease in withdrawal latency and ipsilateral edema formation in carrageenan (100µl vs 50µl)-induced hindpaw inflammation. Common sciatic nerve section of the contralateral side abolished the effect of contralateral pretreatment. Contralateral treatment with local anaesthetics reduced SP-LI concentrations in perfusates following capsaicin challenge, clearly indicating spinal cord mechanisms are involved.