Histaminergic modulation of the intact respiratory network of adult mice

Abstract

Histaminergic modulation of neuronal activity in the respiratory network was investigated under normoxic and hypoxic conditions in the working heart-brainstem preparation of adult mice. Systemic application of histamine, as well as the H-1 and H-3 receptor agonists 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT) and imetit, 0.5-10 micro M, significantly increased the frequency of respiratory burst discharges. Dimaprit, an H-2 receptor agonist, had no effect on respiratory activity. To test for ongoing histaminergic modulation we applied the histamine receptor antagonists pyrilamine (H-1); cimetidine (H-2) and thioperamide (H-3), each 0.5-10 micro M. Only the H-1 receptor antagonist had significant effects, viz. reduction of respiratory frequency and depression of burst amplitude. Underlying effects of histamine receptor activation were identified at the cellular level. Intracellular recordings showed that histamine mediated an increase in synaptic drive potentials in inspiratory neurones while augmentation of inhibitory and excitatory synaptic activity was observed in expiratory neurones. The augmented synaptic depolarisation of inspiratory neurones was blocked by the H-1 receptor antagonist. Histaminergic modulation is also involved in the hypoxic response of the respiratory network. Blockade of H-1 receptors significantly attenuated secondary depression of the biphasic hypoxic responses, while hypoxic augmentation was not affected. We conclude that histamine is a functional neuromodulator, which is tonically active in the respiratory network and is activated further during hypoxia. The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors.

Application of histamine or serotonin to the hypoglossal nucleus increases genioglossus muscle activity across the wake–sleep cycle

“…The central actions of HA are mediated by H 1 , H 2 and H 3 receptor subtypes, with H 1 and H 2 receptors mostly mediating excitatory postsynaptic actions and H 3 receptors, located on histaminergic and non-histaminergic endings, causing autoinhibition of the release and synthesis of HA and other neurotransmitters (Haas and Panula, 2003). A recent study has shown that HA modulates the medullary respiratory network mainly via H 1 receptors (Dutschmann et al, 2003). Although the histaminergic receptor subtypes controlling the activity of HMN remain to be determined, even with the current state of knowledge, our findings of the activating effect of HA might point the way towards a possible pharmacological approach for the treatment of OSA.…”

Time-Dependent Ventilatory Response to Poikilocapnic Hypoxia during Light and Dark Periods and the Role of Histamine H1 Receptors in Mice

“…However, since hypocapnia was weak at 3-10 min after exposure, ventilation would still be sustained according to the metabolic demand in H1RKO mice. Histaminergic modulation during HVD is also illustrated by the evidence that a histamine H1 receptor antagonist reduces HVD for phrenic nerve activity after systemic administration in mice [14]. Thus H1-receptor modulation was obvious in the declined phase in response to poikilocapnic hypoxia.…”

“…Histamine is known as a functional neuromodulator that tonically acts on the respiratory neuron network and is further activated during hypoxia [14]. Histamine affects an inspiratory offswitch level during hypercapnia (5-9% CO 2 ) via H1 receptors [15].…”

Polymorphisms in genes of respiratory control and sudden infant death syndrome

“…Further, excitatory transmitters are cholecystokinin, acting on CCK 1 receptors within one or more medullary or pontine respiratory groups, thyrotropin-releasing hormone, which induces bursting properties in neurons of the Ncl. tractus solitarius, and histamine, acting primarily on H1 receptors [14][15][16]. Primarily, inhibitory modulators are opioids and somatostatin [17].…”