Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus

Abstract

The perifornical (PF) region of the posterior hypothalamus promotes wakefulness and facilitates motor activity. In anesthetized rats, local disinhibition of PF neurons by GABA(A) receptor antagonists activates orexin (OX) neurons and elicits a systemic response, including increases of hypoglossal nerve activity (XIIa), respiratory rate, heart rate, and blood pressure. The increase of XIIa is mediated to hypoglossal (XII) motoneurons by pathways that do not require noradrenergic or serotonergic projections. We hypothesized that the pathway might include OX-dependent activation locally within the PF region or direct projections of OX neurons to the XII nucleus. Adult, male Sprague-Dawley rats were urethane anesthetized, vagotomized, paralyzed, and ventilated. Gabazine (GABA(A) receptor antagonist, 0.18 mM, 20 nl) was injected into the PF region, and ~2 h later, a second gabazine injection was performed preceded by injection of a dual OX1/2 receptor antagonist (almorexant; 90 mM) either into the XII nucleus (40-60 nl at 2-3 rostrocaudal levels; n = 6 rats), or into the PF region (40-60 nl; n = 6 rats). XIIa, respiratory rate, heart rate, and arterial blood pressure were analyzed for 70 min after each gabazine injection. The excitatory effects of PF gabazine on XIIa, respiratory, and heart rates were significantly reduced by up to 44-82% when gabazine injections were preceded by PF almorexant injections, but not when almorexant was injected into the XII nucleus. These data suggest that a significant portion of XII motoneuronal and cardiorespiratory activation evoked by disinhibition of PF neurons is mediated by local OX-dependent mechanisms within the posterior hypothalamus.

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

“…16). However, activation of XII motoneurons elicited by activation of posterior hypothalamic perifornical neurons was not attenuated when the orexin type 2 receptor antagonist, almorexant (15 mg/kg) (62) was injected into the XII nucleus (518). …”

“…One role of endogenous orexin in the control of upper airway motoneurons that has been revealed to date is exerted at the very site where orexin-containing cells are located. Specifically, when almorexant was injected into the posterior hypothalamus prior to activation of posterior hypothalamic cells with the GABA A receptor antagonist, gabazine, the resulting activation of XII motoneurons was delayed and attenuated and the increases in respiratory rate and heart rate were diminished when compared to the effects of hypothalamic gabazine without almorexant pretreatment (518). Collectively, these findings suggest that the effects elicited by disinhibition of cells in the perifornical hypothalamic region originate in both orexin-containing and other neurons with overlapping projections and redundant functions.…”

“…However, physiological and pharmacological studies reveal that nonorexin cells located in the posterior hypothalamic orexinergic region also can significantly influence the respiratory output, including upper airway motoneurons. In particular, neither the combined antagonism of 5-HT and NE-mediated excitation at the XII nucleus level (147), nor microinjections of a dual orexin receptor antagonist into the XII nucleus (518), could significantly attenuate activation of XII motoneurons from the hypothalamic region containing orexin neurons. On the other hand, microinjections of a dual orexin receptor antagonist into the hypothalamic orexin cell field significantly attenuated activation of XII motoneurons from this hypothalamic region (518).…”

Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies

“…Regulation of appetite and stress response [24][25][26] Respiratory effects [27][28][29] Addiction 11,25,26,[30][31][32][33][34][35][36][37][38] Behavioral changes associated with cocaine administration 39 Analgesia 11,40 Food intake regulation 23,41 Central regulation of feeding (of blind cavefish) 42 Regulation of glucose metabolism 43,44 Energy balance regulation 45,46 Insulin secretion regulation 44 Variability in diet-induced obesity sensitivity 47 Proliferation and viability of 3T3-L1 preadipocytes 48 Body temperature regulation 46,49 Neuroendocrine function 6,49,50 Pituitary hormone secretion 51 Cardiovascular activities 49,[52][53][54] Post-ischemic attenuation of inflammatory responses (neuroprotection) 55 Prevention of cerebral ischemic neuronal damage (neuroprotection) 43 Reproduction [56][57]…”

“…For instance, in anesthetized rats, the activation of orexin neurons can be obtained via a local disinhibition of neurons of perifornical region 95 of the posterior hypothalamus neurons by GABA (A) receptor antagonists. 53 Interestedly, the implication of orexin A and orexin B in the regulation of monoaminergic and cholinergic neuron function in wakefulness maintenance has also been reported. 3 Furthermore, orexin application to the rat brain produces serotonergic and cholinergic neuron depolarization, 96,97 and orexin has been shown to modify the synaptic activity of dopamine neurons.…”