TUMOR-NECROSIS-FACTOR ENHANCES THE CAPSAICIN SENSITIVITY OF RAT SENSORY NEURONS

The capacity of the proinflammatory cytokines, tumor necrosis factor a lpha (TNF alpha) and interleukin 1 beta (IL-1 beta), to modulate the s ensitivity of isolated sensory neurons grown in culture to the excitat ory chemical agent capsaicin was examined. Alterations in capsaicin se nsitivity were assessed by quantifying the number of neurons labeled w ith cobalt after exposure to capsaicin and by recording the whole-cell response from a single neuron to the focal application of capsaicin. A 24 hr pretreatment of the neuronal cultures with TNF alpha (10 or 50 ng/ml), but not IL-1 beta (10 or 50 ng/ml), produced a concentration- dependent increase in the number of cobalt-labeled neurons after expos ure to 100 nM capsaicin. The peak increase in the number of labeled ne urons was attained after a 4 hr treatment with 10 ng/ml TNF alpha. Sim ilarly, pretreatment with TNF alpha (10 ng/ml for 4, 12, and 24 hr) pr oduced a greater than twofold increase in the average peak amplitude o f the inward current evoked by 100 nM capsaicin. Both the TNF alpha-in duced increase in labeling and current amplitude were blocked by treat ing the neuronal cultures with indomethacin before the addition of TNF alpha. Enhancement of the capsaicin-evoked current also was blocked b y the specific cyclo-oxygenase-2 inhibitor SC-236. These results indic ate that TNF alpha can enhance the sensitivity of sensory neurons to t he excitation produced by capsaicin and that this enhancement likely i s mediated by the neuronal production of prostaglandins. Isolated sens ory neurons grown in culture may prove to be a useful model system in which to explore how prolonged exposure to mediators associated with c hronic inflammation alter the regulatory pathways that modulate the ex citability of the nervous system.