Activation of 5-HT_1Areceptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet

Abstract

Activation of 5-HT 1A receptors in the medullary raphé decreases sympathetically mediated brown adipose tissue (BAT) thermogenesis and peripheral vasoconstriction when previously activated with leptin, LPS, prostaglandins, or cooling. It is not known whether shivering is also modulated by medullary raphé 5-HT 1A receptors. We previously showed in conscious piglets that activation of 5-HT 1A receptors with (Ϯ)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the raphé that contains substantial numbers of 5-HT neurons, eliminates rapid eye movement (REM) sleep and decreases shivering in a cold environment, but does not attenuate peripheral vasoconstriction. Hoffman JM, Brown JW, Sirlin EA, Benoit AM, Gill WH, Harris MB, Darnall RA. Am J Physiol Regul Integr Comp Physiol 293: R518 -R527, 2007. We hypothesized that, during cooling, activation of 5-HT 1A receptors in the medullary raphé would also eliminate REM sleep and, in contrast to activation of 5-HT 1A receptors in the PGCL, would attenuate both shivering and peripheral vasoconstriction. In a continuously cool environment, dialysis of 8-OH-DPAT into the medullary raphé resulted in alternating brief periods of non-REM sleep and wakefulness and eliminated REM sleep, as observed when 8-OH-DPAT is dialyzed into the PGCL. Moreover, both shivering and peripheral vasoconstriction were significantly attenuated after 8-OH-DPAT dialysis into the medullary raphé. The effects of 8-OH-DPAT were prevented after dialysis of the selective 5-HT 1A receptor antagonist WAY-100635. We conclude that, during cooling, exogenous activation of 5-HT 1A receptors in the medullary raphé decreases both shivering and peripheral vasoconstriction. Our data are consistent with the hypothesis that neurons expressing 5-HT 1A receptors in the medullary raphé facilitate spinal motor circuits involved in shivering, as well as sympathetic stimulation of other thermoregulatory effector mechanisms. thermoregulation; serotonin; brain stem; raphé; the sudden infant death syndrome MANY NEURONS IN THE MEDULLARY raphé, including serotonergic (5-HT) neurons, project to the intermediolateral cell column (IML) of the spinal cord and modulate sympathetic outflow to thermoregulatory effector mechanisms, including brown adipose tissue (BAT) thermogenesis, vasoconstriction of thermoregulatory cutaneous vascular beds, and heart rate (HR) (14,53,58,86,89). Studies in anesthetized and conscious animals have shown that activation of 5-HT 1A receptors in the medullary raphé with the selective agonist, (Ϯ)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), attenuates sympathetic outflow to BAT and peripheral vessels when previously elevated by LPS, leptin, or cooling (11,52,59,63,64).There is mounting evidence that medullary raphé 5-HT neurons modulate sympathetically mediated thermoregulatory mechanisms; however, little is known about the role of medullary raphé 5-HT neurons in shivering thermogenesis. Shivering is an involuntary tremor that i...

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

“…sleep (11,34). Others have described similar shifts to wakefulness after lidocaine injection into the raphe magnus and rostral ventromedial medulla, a region implicated in antinociception (7).…”

“…One study in newborn lambs demonstrated that blockade of opioid receptors did not reverse the progressive lengthening of the time to arousal in response to repeated hypoxia exposures (48). Adenosine is released from cells into the extracellular space during hypoxia when oxygen needs no longer match oxygen supply (16) and activation of both GABA A and serotonin 1A (5-HT 1A ) receptors in this region disrupts sleep and promotes wakefulness (11,13,15,34).Our major objective was to determine whether the time to arousal in response to hypoxia and/or its progressive lengthening (habituation) in response to repeated exposure to hypoxia are mediated or modulated by medullary raphe GABAergic mechanisms. We focused on the medullary raphe because this region has been implicated in the pathogenesis of SIDS (46, 60).…”

“…One study in newborn lambs demonstrated that blockade of opioid receptors did not reverse the progressive lengthening of the time to arousal in response to repeated hypoxia exposures (48). Adenosine is released from cells into the extracellular space during hypoxia when oxygen needs no longer match oxygen supply (16) and activation of both GABA A and serotonin 1A (5-HT 1A ) receptors in this region disrupts sleep and promotes wakefulness (11,13,15,34).…”

Central circuitries for body temperature regulation and fever

“…Injection of 8-OH-DPAT, a 5-HT 1A receptor agonist, into the rMR blocks BAT thermogenic, metabolic, and tachycardic responses to skin cooling (Fig. 7D) or intravenous injection of leptin (92,107), as well as shivering evoked by cooling or PGE 2 injection into the POA (18,106). These sympathoinhibitory effects of 5-HT 1A receptor agonists through their action in the rMR might be a major pharmacological cause of severe hypothermia observed following systemic administration of such drugs in rats (52), mice (43), and humans (11).…”

Introduction

“…It is hoped that this kind of lecture will become a tradition in future PPTR congresses. The lectures were followed by 10 selected symposia which were devoted to the topics of hyperthermia-induced hyperpnea and thermal panting (Entin et al 2005;White 2006;Fujii et al 2008), TRP channels in body temperature regulation (Tajino et al 2007;Gavva et al 2008), heat stroke (Chen et al 2007), acclimation plasticity and limits of heat tolerance (Taylor 2006, Buckley 2007, Horowitz 2008, Matsuzaki et al 2009), thermoregulation and the sudden infant death syndrome (Blair et al 2008;Brown et al 2008;Hodges et al 2008), control and coordination processes within the thermoregulatory system (Romanovsky 2006;Werner et al 2008), mechanisms and mediators of immune-to-brain communication during inXammation (Weiland et al 2007;Harden et al 2008;Rummel et al 2008), neuronal mechanisms contributing to body temperature regulation (Bautista et al 2007;Tanaka et al 2007;Nakamura and Morrison 2008) and adaptive thermogenesis (Nedergaard et al 2007;Wijers et al 2007). The meeting also included a session of the presentation of six young researcher award winners, two sessions of oral presentation (10 speech) and two poster sessions (126 posters).…”