FEVER AND FEEDING - DIFFERENTIAL ACTIONS OF MACROPHAGE INFLAMMATORY PROTEIN-1 (MIP-1), MIP-1-ALPHA AND MIP-1-BETA ON RAT HYPOTHALAMUS

Changes in body temperature (T(b)) and feeding were characterized in unrestrained rats following the micro-injection into the anterior hypothalamic preoptic area (AH/POA) of macrophage inflammatory protein-I (MIP-1), MIP-1alpha or MIP-1beta. After the rats recovered from the stereotaxic implantation of a single guide tube placed in the AH/POA, either one of the MIP-1 compounds or control CSF was micro-injected in a volume of 1.0 mul into this area. Changes in body temperature (T(b)) and food and water intakes were monitored throughout each experiment. When micro-injected into the AH/POA in a dose of 28 or 280 pg, doublet MIP-1 and MIP-1beta evoked a monophasic fever which increased above baseline to a mean maximum of 2.17 +/- 0.14-degrees-C and 2.1 +/- 0.24-degrees-C, respectively. MIP-1alpha. micro-injected similarly evoked a biphasic fever, with the T(b) declining transiently at the 30 min point greater-than-or-equal-to 0.4-degrees-C lower than the congruent rises in T(b) evoked by doublet MIP-1 or MIP-1beta. The secondary rise in T(b) induced by MIP-1alpha had a latency of 1.5-2.0 hrs and reached a maximum of 1.56 +/- 0.16-degrees-C. Although all three cytokines significantly attentuated the rats' mean intake of food during the 24 hr interval after their micro-injection into the AH/POA, doublet MIP-1 exerted the most potent anorexic effect in comparison to that of the saline control rats. However, neither body weight nor intake of water was altered significantly by the three cytokines. These results demonstrate a functional distinction between the febrile actions of MIP-1alpha nd MIP-1beta on cells of the AH/POA. It is envisaged that MIP-1beta underlies the initial phase of a pyrogen-induced fever, whereas MIP-1alpha could mediate the secondary phase of a biphasic fever. Clearly, the localized elevation of either MIP-1alpha or MIP-1beta in the AH/POA perturbs the neuronal mechanism underlying the ''set-point'' for body temperature. Thus, both MIP-1alpha and MIP-1beta could play a functional role in the pathological events occurring in neurons of the AH/POA in response to an endotoxin or other pyrogen challenge.