Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro

Abstract

Neuronal networks in the medulla oblongata generate respiratory rhythm in mammals. The pre-B otzinger complex (Smith et al. 1991) in the rostral ventrolateral medulla oblongata (RVL) (Onimaru et al. 1988) has been proposed to be the crucial site of this rhythmogenesis, but the detailed organization of this noed vitale is still unknown. The unique patterns of receptors and membrane channels expressed by specific types of neurones, and interaction between these neurones, maintains the central pattern generator for respiration. Thus it is important to increase our understanding of the receptors and membrane channels in each type of cell in this neuronal network. One of the central modulators of respiration is adenosine, whose action is especially important around the time of birth (Runold et al. 1986; Irestedt et al. 1989;Herlenius et al. 1997). Adenosine has been proposed to be involved in the suppression of fetal and neonatal breathing (Lagercrantz et al. 1984;Bissonnette et al. 1991;Herlenius et al. 1997), particularly during hypoxia when extracellular levels of this nucleoside rapidly increase (Winn et al. 1981). Furthermore, blocking A1-receptors with xanthine derivatives abolishes or attenuates hypoxia-induced depression of breathing in newborn mammals (Runold et al. 1989;Neylon & Marshall 1991;Kawai et al. 1995). Thus blocking the action of endogenous adenosine is probably the mechanism by which theophylline exerts its clinical effects in the treatment of apnoea of prematurity. Adenosine plays multiple roles throughout the nervous system (Brundege & Dunwiddie, 1997), e.g. inhibiting excitatory postsynaptic currents in hippocampal neurones (Katchman & Hershkowitz, 1993) and decreasing neurotransmitter release in prejunctional motoneurones (Mynlieff & Beam, 1994). As recently reported, stimulation of brainstem adenosine A1-receptors depresses the activity of

P2Y1Receptor Modulation of the Pre-Bötzinger Complex Inspiratory Rhythm Generating NetworkIn Vitro

“…In respiratory networks, adenosine is clinically significant because it depresses ventilation (Herlenius et al, 1997;Herlenius and Lagercrantz, 1999;Mironov et al, 1999), and is implicated in the hypoxia-induced depression of ventilation (Yan et al, 1995) and apnea in newborns (Runold et al, 1989;Lopes et al, 1994). Our observation that the post-ATP decrease in frequency depends on ATP breakdown suggests that effects of ATP on rhythm will be determined by an interaction between P2 and P1 receptors.…”

“…1 A). Given that extracellular ATP is rapidly hydrolyzed by ectonucleotidases to ADP and adenosine (Zimmermann, 2000(Zimmermann, , 2001, which is an inhibitory modulator of respiratory frequency (Herlenius et al, 1997;Herlenius and Lagercrantz, 1999), we tested whether the post-ATP inhibition of frequency results from the hydrolysis of ATP. We compared the effects on frequency of microinjecting into the preBötC ATP and ATP␥s, a nonhydrolysable analog of ATP.…”

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1receptor

“…This in vivo response can be studied in the deafferented brainstem in vitro (24). It has been suggested that adenosine contributes to this depression by acting on brainstem neurons (25). This suggestion provides a rationale for the use of methylxanthines to reduce the number of neonatal apneas.…”

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

“…Adenosine, conversely, is an agonist at P1Rs in which the effect that has been primarily reported in fetal and neonatal animals to inhibit frequency through an A 1 R mechanism (Lagercrantz et al, 1984;Herlenius and Lagercrantz, 1999). Its effects, however, are confounded by possible actions at excitatory A 2a receptors, and developmental studies have yielded inconsistent results (Yamamoto et al, 1994;Kawai et al, 1995;Herlenius and Lagercrantz, 1999;Mironov et al, 1999;Brockhaus and Ballanyi, 2000;Wang et al, 2005;Mayer et al, 2006).…”

“…ADP is a P2YR agonist (Burnstock, 2006) and, therefore, could excite preBötC networks (Lorier et al, 2007). ADO is a P1R agonist whose actions are unclear, but, in premature and neonatal mammals, it is primarily reported to inhibit breathing (Herlenius et al, 1997(Herlenius et al, , 1999(Herlenius et al, , 2002. It is also implicated in apnea of prematurity (Bhatt-Mehta and Schumacher, 2003).…”