Optimal interaction of respiratory and thermal regulation at rest and during exercise: Role of a serotonin-gated spinoparabrachial thermoafferent pathway

Abstract

Recent evidence indicates that the lateral parabrachial nucleus (LPBN) in dorsolateral pons is pivotal in mediating the feedback control of inspiratory drive by central chemoreceptor input and feedforward control of body temperature by cutaneous thermoreceptor input. The latter is subject to descending serotonergic inhibition which gates the transmission of ascending thermoafferent information from spinal dorsal horn to the LPBN. Here, a model is proposed which suggests that the LPBN may be important in balancing respiratory and thermal homeostasis, two conflicting goals that are heightened by environmental heat/cold stress or exercise where the effects of respiratory thermolysis become prominent. This optimization model of respiratory-thermoregulatory interaction is supported by a host of recent studies which demonstrate that animals with serotonin (5-HT) dysfunction at the spinal dorsal horn—due to 5-HT antagonism, genetic 5-HT defects or spinal cord injury—all display similar respiratory abnormalities that are consistent with hyperactivity of the spinoparabrachial thermoafferent (and pain) pathway.

A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing

“…The present results provide the first direct experimental evidence revealing a latent (i.e., persistently active in the quiescent state without explicit sensory provocation) 5-HT 1A R-gated spinal afferent pathway (or collection of pathways) which exerts profound tonic inhibitory influence on respiration, as conjectured previously (Poon 2009). Our results with lumbar-intrathecal 8-OH-DPAT injection after siRNA knockdown of 5-HT 1A R unequivocally localized the site of action of 8-OH-DPAT to (pre-and/or postsynaptic) 5-HT 1A Rs in the superficial layers of spinal dorsal horn at the lumbar level and not cervical level or higher.…”

“…Most previous studies have ascribed the complex excitatory-inhibitory effects of systemic 5-HT 1A R agonists on breathing exclusively to their actions in brainstem respiratory-related networks (Lalley et al 1994;Wilken et al 1997;Sahibzada et al 2000;El-Khatib et al 2003;Teng et al 2003;Choi et al 2005;Abdala et al 2010;Zhuang et al 2012;Corcoran et al 2014). However, conflicting evidences reported in the literature have led to the hypothesis that the excitatory effect of 5-HT 1A R activation on breathing may be attributed in part to disfacilitation of a latent 5-HT 1A R-gated spinal afferent pathway which normally exerts a paradoxical tonic inhibitory effect on breathing even in the quiescent state without explicit sensory provocations (Poon 2009). Here, we employed small-interfering RNA (siRNA) technology to unequivocally verify the respiratory-inhibiting effect of a hitherto unrecognized 5-HT 1A Rgated spinal afferent pathway and to localize the site of action to 5-HT 1A Rs in lumbar spinal cord dorsal horn.…”

Novel Modeling of Work of Breathing for Its Optimization During Increased Respiratory Efforts

“…This model has been used in studies related to respiratory modeling not only by the same author [28,36,37] but also by others [38,39,40]. Recently, several studies have used its cost functions to determine the breathing pattern in subjects under assisted mechanical ventilation [39,41,42,43].…”

“…Recently, several studies have used its cost functions to determine the breathing pattern in subjects under assisted mechanical ventilation [39,41,42,43]. The WOB depended on model parameters whose values were not provided in any of the previous studies [9,28,36,37,38,39,40,41,42,43], which suggests that respiratory control modeling based on optimization criteria needs additional experimental and computational efforts. In addition, two different functions were also proposed in [9] to measure the mechanical cost.…”

Exercise Ventilation-CO2Output Relationship in COPD and Heart Failure: A Tale of Two Abnormalities

“…The answer to this critical question may call for a fundamental paradigm shift in viewing the brain mechanism for ventilatory control not as a simplistic knee-jerk reflex driver but as a self-adaptive intelligent controller capable of balancing such chemical and mechanical constraints in determining the optimal V E that meets the metabolic demand without causing excessive work of breathing. [12][13][14][15][16] In this light, patients with chronic heart failure, COPD, and other diseases may actually be much smarter in optimizing their breathing for self-survival than they have been traditionally given credit for in practice.…”