Hypothalamic indomethacin fails to block fever induced in rats by central macrophage inflammatory protein-1 (MIP-1)

Abstract

This investigation examined the extent to which the activity of a prostaglandin (PG) in the anterior hypothalamic, preoptic area (AH/POA) of the rat plays a role in the intense feverr induced by macrophage inflammatory protein-1 (MIP-1) applied directly to this anatomical region. For the microinjection of both a PG synthesis inhibitor, indomethacin, and MIP-1 into sites within the AH/POA, guide cannulae were implanted chronically just above this pyrogen-reactive region. Postoperatively, the body temperature (T b) of each rat was monitored in the inrestrained condition by means of a colonic thermistor probe. MIP-1 microinjected into the AH/POA in a 0.5-μl volume evoked a biphasic fever when given in a dose of 5.6 picograms (pg) and a monophasic fever in a dose of 28 pg. The latency of the febrile response was ordinarily 15 min with an asymptote of 1.5°C reached ordinarily within 2.0–2.5 h. When the cytokine-reactive site in the AH/POA was pretreated with indomethacin microinjected in an efficacious dose of 0.5 μg, the MIP-1 fever evoked by 5.6 pg was not inhibited. Further, pretreatment of AH/POA sites with indomethacin prior to the higher 28-pg dose of MIP-1 delayed the febrile response but did not block it. As a systemic control, indomethacin also was administered intraperitoneally in a dose of 5.0 mg/kg, again 15 min prior to the microinjection of MIP-1 into the AH/POA. In this case, indomethacin only partially attenuated but did not block the fever evoked by either dose of MIP-1. These results suggest that, although the synthesis of a PG in the periphery could contribute to the central pyrexic action of MIP-1, this cytokine exerts its febrile action within thermosensitive and pyrogen-reactive neurons independently of the local synthesis and/or release of a PG of the E type. Therefore, it is evident that a PGE-independent mechanism within the AH/POA participates in the sequence of cellular events underlying the pathogenesis of a centrally mediated febrile response.