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The effects of intracerebroventricular (i.c.v.) injection of histamine (HA), an H1-agonist (2-pyridylethylamine, 2PEA) and an H1-antagonist (pyrilamine, PYR) on hot-plate latency in rats were examined. HA (40 or 80 μg/rat) significantly enhanced the pain threshold whereas 2PEA (80 or 160 μg/rat) and PYR (20 μg/rat) had no effect. Moreover, PYR did not modify HA antinociception. These results indicate that HA-H1 receptors are not involved in the inhibition by HA of the hot-plate response. To characterize the neural pathways involved in the antinociceptive action of HA, the effect of HA (40 μg/rat, i.c.v.) on the firing of thalamic neurons in arthritic rats evoked by peripheral noxious stimuli was recorded by electrophysiological techniques. HA markedly depressed the neuronal firing evoked by ankle mobilization, suggesting that the thalamus is one important area involved in modulation of pain by HA.

The effects of intracerebroventricular (icv) injection of histamine (HA, 0.4 μmol/rat) or of the inhibitor of HA synthesisα-fluoromethylhistidine (αFMH, 100 mg/kg, intracarotid (ia)) on growth hormone (GH) secretion induced by GH-releasing hormone (hGHRH1–40, 2 μg/kg, ia) in freely moving rats were examined. HA significantly inhibited GH release induced by GHRH whereas pretreatment (3 h before) with αFMH enhanced the GH response to GHRH.

The effects of intracarotid (i.a.) administration of the histamine (HA) H3-receptor agonist (R)-alpha-methyl-histamine (alpha MeHA) and of the H3-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H3-drugs. Neither THIO (2.5 mg/kg) nor alpha MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. alpha MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and alpha MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicated that endogenous brain HA facilitates PRL and inhibits GH secretion.

We studied the effects of histamine (HA) antagonists on the facilitatory action of morphine (M) and beta-endorphin (beta E) on prolactin (PRL) release and the effect of alpha-fluoromethylhistidine (alpha-FMH, inhibitor of HA synthesis) on beta E-induced PRL secretion. Male rats were injected intracerebroventricularly (i.c.v.) with mepyramine (MEP, H1-antagonist, 0.8 mumol/rat) or ranitidine (RAN, H2-antagonist, 0.4 mumol/rat) 10 min before M (6 mg/kg, intracarotid, i.a.) or beta E (0.25 micrograms/rat, i.c.v.). alpha-FMH (200 micrograms/rat, i.c.v.) was administered 3 h before beta E. Plasma PRL levels were measured at various times before and after drug treatment. RAN but not MEP significantly reduced PRL release induced by M whereas neither HA-antagonists nor alpha-FMH modified beta E-induced PRL release. The results obtained show that brain HA contributes through activation of H2-receptors to the PRL facilitatory action of M but not of beta E.

The effects of intracerebroventricular injection of histamine H2-receptor agonists (4-methylhistamine, 4-MeH; dimaprit, DIM), H2-antagonists (cimetidine, CIM; ranitidine, RAN; famotidine, FAM) and of the DIM chemical analogue SKF 91487 on hot-plate latency in rats were examined. Both DIM (0.4-0.8 mumol/rat) and 4-MeH (0.4-0.8 mumol/rat) significantly enhanced the pain threshold, whereas SFF 91487 (0.8 mumol/rat) had no effect, indicating that DIM antinociception is specifically due to its activity on histamine (HA) receptors. The H2-antagonists CIM (0.8 mumol/rat) and RAN (0.6 mumol/rat) also enhanced the pain threshold, while FAM (0.03 mumol/rat) did not modify pain latency. When injected before 4-MeH, FAM reduced the antinociceptive effect of 4-MeH. These findings suggest that the antinociceptive activity of CIM and RAN is not related to specific blockade of H2-receptors and that the activation of HA-H2-receptors is inhibitory to nociception.

We examined the effects of an irreversible inhibitor of brain histamine (HA) synthesis, alpha-fluoromethyl-histidine (alpha-FMH), on prolactin (PRL) release induced by an opiate agonist (morphine, M) or by a serotonergic agonist (MK212). alpha-FMH was administered intracerebroventricularly (i.c.v., 200 micrograms/rat) into freely moving rats with indwelling catheters in the carotid. M (6 mg/kg, intracarotid, i.a.) was administered simultaneously with or 3 h after alpha-FMH. MK212 (2.5 mg/kg, i.a.) was administered 3 h after alpha-FMH. Blood samples for assay for PRL were drawn at 0, 10, 20, 40 min after M or MK212 administration. alpha-FMH (3 h before) significantly reduced the PRL-releasing effect of M and MK212 but did not modify PRL release by M when administered simultaneously. The present results showing that the facilitatory actions of the opiate and serotonergic systems on PRL are impaired when brain HA synthesis is reduced, suggest that there is an HA-dependent step in opiate and serotonergic control of PRL.