Molecular biological and pharmacological study on the roles of brain interleukin-1 in transmission and regulation of nociceptive information

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In this study, we conducted the following expeiments to elucidate the roles of brain interleukin-1beta in the modulation of nociceptive information. First, IL-1beta was intracerebroventriculary administrated and the nociceptive threshold to mechanical stimulation was measured. The lower doses (10,000 pg) of IL-1beta induced hyperalgesia, but the higher doses (1,10 ng) of IL-1beta induced analgesia. These effects of IL-1beta on the nociceptive threshold were inhibited by the simultaneous administration of IL-1 receptor antagonist.Hyperalgesia induced by the lower dose of IL-1beta but not analgesic effects by the higher dose of IL-1beta, was suppressed by pretreatment of sodium salicylate. Pretreatment of alpha-helical-CRF inhibited both hyperalgesic and analgesic effects of IL-1beta. Secondly, we examined the distribution of IL-1 receptor mRNA in the rat brain using in situ hybridization technique. Type I IL-1 receptor mRNA was observed in the several nuclei of the thalamus, amygdala and medulla. In these nuclei type I IL-1 receptor mRNA was localized on the neuronal cells which express neuron specific enolase mRNA.Type II IL-1 receptor mRNA was not observed in the normal rat brain. As regard for IL-1beta converting enzyme , a key enzyme for processing the IL-1beta precursor protein to produce mature IL-1beta, its mRNA was not detected in the normal rat brain. Furthermore, an administration of isoproterenol, which had been shown to induce IL-1beta mRNA in the rat hypothalamus, caused significant expression of IL-1beta mRNA at 1 hr after administration in several brain regions. In addition, analgesic effects of isoproterenol were observed. Lastly, increased expression of IL-1beta mRNA was observed in the hypothalamus after i.p.l.administration of formalin, which induced sustained pain. These data strongly suggest that IL-1beta is involved in the regulation of nociceptive information in the brain.