TRPV1 channels in the nucleus of the solitary tract mediate thermal prolongation of the LCR in decerebrate piglets

Abstract

Elevating body temperature or just the temperature of the dorsal medulla by approximately 2 °C prolongs the laryngeal chemoreflex (LCR) in decerebrate neonatal piglets. We tested the hypothesis that transient receptor potential vanilloid 1 (TRPV1) receptors in the nucleus of the solitary tract (NTS) mediate thermal prolongation of the LCR. We studied the effect of a selective TRPV1 receptor antagonist on thermal prolongation of the LCR, and we tested the effect of a TRPV1 agonist on the duration of the LCR under normothermic conditions. We studied 37 decerebrate neonatal piglets between the ages of post-natal days 4 and 7. The TRPV1 receptor antagonist, 5−iodoresiniferatoxin (65 microM/L in 100 nL), blocked thermal prolongation of the LCR when injected bilaterally into the region of the NTS. The TRPV1 agonist, resiniferatoxin (0.65-1.0 mM/L in 100 nL), prolonged the LCR after bilateral injection into the NTS even when the body temperature of each piglet was normal. The effect of the TRPV1 agonists could be blocked by treatment with the GABA A receptor antagonist, bicuculline, whether given intravenously (0.3 mg/kg) or focally injected bilaterally into the NTS (10 mM in 100nL). We conclude that TRPV1 receptors in the NTS mediate thermal prolongation of the LCR.

Interleukin-1β and interleukin-6 enhance thermal prolongation of the LCR in decerebrate piglets

“…However, TRPV1 channel activation in the NTS, which enhances asynchronous release of glutamate following visceral afferent stimulation, was thermally modulated by temperatures between 25 and 38 °C (Peters et al, 2010). Consistent with this more physiological TRPV1 thermal threshold of activation, elevating body temperature in neonatal piglets by 1–2 °C was sufficient to elicit a TRPV1-dependent thermal prolongation of the LCR (Xia et al, 2011). Thus, the activity of TRPV1 channels in the NTS was modulated at temperatures well within the physiological range in neonatal animals.…”

“…IL-1β pretreatment increased the duration of apnea elicited either by inhalation of ammonia or laryngeal instillation of hydrochloric acid in anesthetized piglets even when body temperature was held constant (Frøen et al, 2000; Stoltenberg et al, 1994). These authors speculated about the possible mechanism of this effect, but since the role of TRPV1 in the regulation of the LCR was described (Xia et al, 2011), we can propose a mechanistically plausible, molecular chain of events between IL-1β and control of the LCR. TRPV1 channels are temperature sensitive, and particularly interesting, for that reason, in respect to the thermal prolongation of the LCR.…”

“…These second order neurons express non-NMDA glutamate receptors, and when visceral afferents are stimulated, glutamatergic excitatory post-synaptic currents (EPSCs) are elicited in the second order neurons (Doyle et al, 2002; Jin et al, 2004; Peters et al, 2010), and elicit apnea. In previous studies, we have focused on laryngeal stimuli and central regulatory pathways that emphasize the role of C-fiber modulation of the LCR (Xia et al, 2011). …”

“…is a risk factor for SIDS, and elevated body temperature enhanced laryngeal adduction induced by superior laryngeal nerve stimulation in dogs (Haraguchi et al, 1983) and prolonged the LCR elicited by injection small volumes of water into the larynx in decerebrate piglets (Curran et al, 2005). The effect of elevated body temperature on the LCR depends on activation of TRPV1 receptors within the nucleus of the tractus solitarius (NTS) (Xia et al, 2011). A recent history of an upper respiratory tract infection (URI) is also a risk factor for SIDS (Steinschneider, 1972), and viral infections, particularly respiratory syncytial virus infections, may prolong reflex apneas in newborn lambs (Lindgren and Grogaard, 1996; Lindgren et al, 1992).…”

Vanilloids selectively sensitize thermal glutamate release from TRPV1 expressing solitary tract afferents

“…The LCR triggers an airway-protective reflex by inducing prolonged apnea, swallowing, and coughing (Curran et al , 2005). A focal 2–2.5°C temperature increase to the NTS sub region facilitated the reflex apnea, and this sensitization could be ameliorated by microinjection of 5’iodoresiniferatoxin, an RTX-based TRPV1 antagonist (Curran et al , 2005; Xia et al , 2007; Xia et al , 2011). Given the ability of TRPV1 to transduce inflammatory signals, TRPV1 in ST afferents offers a potential mechanistic frame work for the well-established clinical risk factors for sudden infant death syndrome including hyperthermia and infection (Leiter & Bohm, 2007; Kinney & Thach, 2009).…”