Neuro-humoral mechanisms of relexive respiratory suppression mediated by endogenous opiated system.

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Our previous works have revealed naloxone-reversible respiratory suppression induced by stimulation of thin-fiber muscular afferents: polymodal receptor inputs. The present work is aimed to elucidate the following questions provided by those previous works. 1)Whether N. parabrachialis (PBN) is implicated in the respiratory inhibition, since previous decerebration experiment suggested the importance of the rostral pons. 2)What kinds of modulation factors are involved, since repeated stimulation reduced the magnitude of the respiratory inhibition. 3) What opioid peptide(s) may be really concerned. In addition the receptor characteristics of polymodal receptors are investigated in detail.Results. 1)Both repetitive electrical stimulation of PBN and microinjection of morphine into PBN produced naloxone-reversible, long lasting respiratory supression, which is similar to that induced by peripheral muscular afferent stimulation. 2)Respiratory suppression produced by morphine did not reduce by its repetitive application, suggesting that opioid tolerance is not the cause of the tachyphylaxis of the reflex res[piratory suppression. Since the tachyphylaxis was antagonized by proglumide, an antagonist of cholecystokinin (CCK), it may be caused by a temporal summation of activities in facilitatory systems such as CCK, which would be simultaneously stimulated by muscular afferents. Effectiveness of the stimulation was shown to be respiratoy-phase dependent; influence of vagal inputs was also suggested. 3)Perfusion through the 4th ventricle-cisterna magna with solution containing enkephalinase inhibitors caused significantly larger reflex respiratory suppression. Concentration of enkephalin determined by ELISA was higher in the elute during and after stimulation than before.The present result reveals an enkephalinergic respiratory regulation mechanism triggered by peripheral polymodal receptor inputs.