Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation

CNI-1493 is a potent anti-inflammatory agent, which deactivates macrophages and inhibits the synthesis of proinflammatory mediators. The objective of the present study was to identify the role of the central nervous system (C NS) and efferent vagus nerve signaling in CNI-1493-mediated modulation of a cute inflammation in the periphery. CNI-1493 was administered either intrac erebroventricularly (i.c.v., 0.1-1000 ng/kg) or intravenously (i.v., 5 mg/k g) in anesthetized rats subjected to a standard model of acute inflammation (subcutaneous (s.c.) injection of carrageenan). I.c.v. CNI-1493 significan tly suppressed carrageenan-induced paw edema, even in doses at least 6-logs lower than those required for a systemic effect. Bilateral cervical vagoto my or atropine blockade (I mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 mug/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intac t vagus nerve is required for CNI-1493 activity. Recording of the efferent vagus nerve activity revealed an increase in discharge rate starting at 3-4 min after CNI-1493 administration (5 mg/kg, i.v.) and lasting for 10-14 mi n (control activity=87+/-5.4 impulses/s versus CNI-1493-induced activity=22 9+/-6.7 impulses/s). Modulation of efferent vagus nerve activity by electri cal stimulation (5 V, 2 ms, 1 Hz) of the transected peripheral vagus nerve for 20 min (10 min before carrageenan administration and 10 min after) also prevented the development of acute inflammation. Local administration of t he vagus nerve neurotransmitter, acetylcholine (4 mug/kg, s.c.), or choline rgic agonists into the site of carrageenan-injection also inhibited acute i nflammation. These results now identify a previously unrecognized role of e fferent vagus nerve activity in mediating the central action of an anti-inf lammatory agent. (C) 2000 Published by Elsevier Science B.V.