An adenosine A_2A agonist injected in the nucleus of the solitary tract prolongs the laryngeal chemoreflex by a GABAergic mechanism in decerebrate piglets

Abstract

Hyperthermic prolongation of the laryngeal chemoreflex (LCR) in decerebrate piglets is prevented or reversed by GABA A receptor antagonists and adenosine A 2A (Ad-A 2A ) receptor antagonists administered in the nucleus of the solitary tract (NTS). Therefore, we tested the hypothesis that enhanced GABA A activity and administration of the Ad-A 2A agonist, CGS-21680, would prolong the LCR in normothermic conditions. We studied 46 decerebrate piglets ranging from 3 to 8 postnatal days of age. Focal injection into the NTS of 100 nl of 0.5 m nipecotic acid, a GABA reuptake inhibitor, significantly (P < 0.05) prolonged the LCR in normothermic conditions in 10 of 11 animals tested. Injecting 100 nl of 5-12.5 μm CGS-21680 unilaterally or bilaterally into the NTS also prolonged the LCR in normothermic conditions (n = 15), but the effect was smaller than that of unilateral injection of nipecotic acid. Systemic administration of the GABA A receptor antagonist, bicuculline, prevented the CGS-21680-dependent prolongation of the LCR in normothermic animals (n = 11). We conclude that thermal prolongation of the LCR depends on a thermally sensitive process or set of neurons in the NTS, which, when activated by elevated brain temperature, enhances adenosinergic and GABAergic function in the region of the NTS. These results emphasize the importance of a thermally sensitive integrative site in the dorsal medulla that, along with sites in the ventral medulla, determine the response to laryngeal chemoreflex stimulation.

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

“…In previous studies of the thermal modulation of the LCR in decerebrate piglets, we have seen variable effects on respiratory frequency; the effects were often attributed to elevated body temperature, but sometimes attributable to drug treatments (Duy et al, 2010). In the current study, IL-1β treatment did not affect respiratory frequency (there was no drug treatment effect or drug treatment by temperature effect).…”

“…We have discussed the limitations of studying the LCR in decerebrate neonatal piglets in previous studies (Duy et al, 2010; Xia et al, 2008). We pointed out in these discussions that thermal stress has been identified as a risk factor for SIDS, but this does not mean necessarily that infants who died of SIDS had an elevated body temperature.…”

“…The apnea and LCR durations were not normally distributed, and the variances among treatments were not homogenous; both of which violate the assumptions upon which the ANOVA is based. Therefore, apnea and LCR durations were log-transformed for the statistical analysis, as we have done previously (Curran et al, 2005; Duy et al, 2010), and the ANOVA was performed on the log-transformed data. Data are presented in the text and figures as the mean ± the standard error of the mean of the untransformed values of each variable.…”

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

“…We studied 14 animals in this group, but two of the animals did not demonstrate any thermal prolongation of the LCR. This presents two difficulties: we cannot compare the drug response to the thermal response (since there was no thermal response), and perhaps more interestingly, animals that lack a thermal response have consistently not responded to any of the drug treatments that we have studied (Duy et al, 2010). For these reasons, results from these animals were excluded from analysis.…”

“…The apnea and LCR durations were not normally distributed, and these data did not conform to the assumption of sphericity (one of the assumptions upon which the ANOVA is predicated). Therefore, these data were log transformed for the statistical analysis, as we have done previously (Curran et al, 2005; Duy et al, 2010), and the ANOVA was performed on the log transformed data for these two variables. Data are presented as the mean ± the standard error of the mean.…”