INSULIN HYPOGLYCEMIA-INDUCED ADRENOCORTICOTROPIN AND BETA-ENDORPHIN RELEASE - INVOLVEMENT OF HYPOTHALAMIC HISTAMINERGIC NEURONS

We have previously found that histamine (HA) is involved in the mediat ion of restraint- and ether stress-induced release of the POMC-derived peptides ACTH and beta-endorphin (beta-END). In the present study we investigated the possible involvement of hypothalamic histaminergic ne urons in the mediation of insulin/hypoglycemia-induced release of ACTH and beta-END in conscious male rats. To do so, hypoglycemia stress wa s performed during 1) inhibition of HA synthesis, 2) activation of inh ibitory presynaptic HA H-3-autoreceptors, or 3) blockade of postsynapt ic HA H-1- or H-2-receptors. Hypoglycemia (plasma glucose, 2.2 +/- 0.3 nmol) induced by insulin (3 IU/kg, ip) caused a 3- to 5-fold increase in the plasma concentrations of ACTH and beta-END. A negative exponen tial correlation was found between the plasma glucose concentration an d the ACTH and beta-END levels. Pretreatment of the animals with the H A synthesis inhibitor alpha-fluoromethylhistidine (1.0 mumol) intracer ebroventricularly (icv) in a lateral ventricle, inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 60%. When administered ip (100 mumol/kg), the synthesis inhibitor decreased the beta-END resp onse 50%, but did not affect ACTH secretion significantly. Pretreatmen t of the rats with the H-3-receptor agonist R(alpha)methylhistamine (5 0 mumol/kg, ip, twice) inhibited the secretory responses of ACTH and b eta-END to insulin/hypoglycemia by 60-80%. This inhibitory effect of R (alpha)methylhistamine was reversed by prior administration of the spe cific H-3-receptor antagonist thioperamide. Administration of the H-1- antagonists mepyramine and cetirizine dose-dependently inhibited the A CTH and beta-END responses to insulin/hypoglycemia, with the highest d ose (mepyramine, 350 nmol, icv; cetirizine, 40 mumol/kg, ip) inhibitin g the response by 80-100%. The H-1-antagonist SKF-93944 (226 nmol, icv ) inhibited the ACTH response, but had no effect on the beta-END respo nse. Administration of the H-2-antagonists cimetidine (400 nmol, icv) and ranitidine (400 nmol, icv) inhibited the ACTH and beta-END respons es to insulin/hypoglycemia by 50-80%. We conclude that histaminergic n eurons are involved in the mediation of the insulin/hypoglycemia-induc ed release of ACTH and beta-END and that the effect is mediated via ac tivation of primarily postsynaptic H-1-receptors and, to a lesser exte nt, H-2-receptors.