Contribution of the sensory nervous system : an experimental study in the rat

Abstract: The pathophysiological background to burn induced inflammatory reactions is poorly understood and present therapy options are limited. A model of thermal injury was developed to enable investigations of the acute inflammatory reactions in the periphery as well as of the transmission of nociception at the spinal cord level. Scalding was induced in anaesthetized rats by unilateral immersion of the hindpaw into water at 60°C for varying durations. Ten seconds of heat expo- sure produced no edema measured by plethysmographic volume changes whereas 20 and 30 seconds induced significant ipsilateral edema formation. Using on-line laser Doppler flowmetry, scalding was followed by an immediate phase of perfusion increase and a secondary phase of increased microcirculation after another 30 minutes as the edema reaction was initiated. Radioimmunoassay analyses of paw perfusates showed concentrations of the tachykinin-neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) to be increased after scalding. The nervous system's contribution was revealed in experiments where animals underwent unilateral peripheral nerve-ligation 10 days before scalding. Nerve-ligated rats scalded bilaterally had less swelling on the ligated side as compared to the non-ligated which showed the same progression of volume in- crease as seen in intact rats. NKA immunoreactivity was almost undetectable in the perfusates of mononeuropathic rats, suggesting that the neuropeptide has a contributory role to thermally induced inflammation. The contribution of the tachykinins substance P (SP), NKA and CGRP to thermally induced circulatory and edemic reactions was shown in studies using antagonists towards NK1, NKNY2 and CGRP receptors. Intravenous administration of the neuropeptide antagonists significantly reduced the primary increase of microcirculation after scalding and the secondary phase was almost abolished. Edema was lessened by the use of lo- cally applied NK1 and NK2 antagonists 45 minutes after scalding. In all investigations unilateral thermal injury was followed by bilateral decreases of hindpaw withdrawal latencies (HWL) to mechanical stimulation. In addition, elevated concentrations of CGRP were found in cerebrospinal fluid. Significant increases of HWLs were measured in rats treated by intrathecal administration of the CGRP antagonist, CGRP8-37. These effects were reversed by intrathecal administration of naloxone and by treatment with selective opioid antagonists directed towards g and 8 receptors. In other studies, intrathecally applied NK1 and NK2 receptor antagonists were followed by increased HWLs. The use of a non-peptidergic tachykinin receptor antagonist showed similar effects. Conclusion. Thermal injury induces severe inflammatory reactions. Our studies demonstrate a contributory role of the nervous system and the release of sensory neuropeptides. By modulation of activity in the nervous system both edema formation and nociceptive transmission can be reduced. The knowledge may lead to the development of new treatment strategies.