Opioid-Induced Quantal Slowing Reveals Dual Networks for Respiratory Rhythm Generation

Abstract

Current consensus holds that a single medullary network generates respiratory rhythm in mammals. Pre-Bötzinger Complex inspiratory (I) neurons, isolated in transverse slices, and preinspiratory (pre-I) neurons, found only in more intact en bloc preparations and in vivo, are each proposed as necessary for rhythm generation. Opioids slow I, but not pre-I, neuronal burst periods. In slices, opioids gradually lengthened respiratory periods, whereas in more intact preparations, periods jumped nondeterministically to integer multiples of the control period (quantal slowing). These findings suggest that opioid-induced quantal slowing results from transmission failure of rhythmic drive from pre-I neurons to preBötC I networks, depressed below threshold for spontaneous rhythmic activity. Thus, both I (in the slice), and pre-I neurons are sufficient for respiratory rhythmogenesis.

Chaotic dynamics of resting ventilatory flow in humans assessed through noise titration

“…A neural source for respiratory chaos is a likely hypothesis, because it is widely accepted that the central respiratory command depends on at least two coupled oscillators (see review in Feldman et al, 2003;Mellen et al, 2003; see also Vasilakos et al, 2005). Compound neural oscillator models of the mammalian respiratory rhythm can exhibit complex dynamical behaviors under various periodic inputs (Matsugu et al, 1998), and the study of breath-to-breath variations in tidal volume, end-tidal O 2 and end-tidal However, nonlinearities in the flow pattern could also be created, or altered, by the nature of the media to which the respiratory neural command is applied.…”

Large lesions in the pre-Bötzinger complex area eliminate eupneic respiratory rhythm in awake goats

“…In addition, in vivo studies in anesthetized or decerebrate cats or rats demonstrate that lesioning of the pre-BötzC results in transient (24) or irreversible (7, 10, 18) elimination of eupneic respiratory activity. Further demonstrating the importance of the pre-BötzC in control of breathing was a study showing that Ͼ80% destruction of neurokinin-1 receptor (NK1R)-expressing neurons in the pre-BötzC resulted in an ataxic breathing pattern and hypoventilation in awake rats (6).Recently, it has been proposed that, within the medulla, there are two respiratory rhythm generators, which are mutually inhibitory and each capable of generating a rhythm under different conditions: one is an inspiratory generator composed of pre-BötzC inspiratory neurons, and the second is an expiratory generator composed of preinspiratory (pre-I) neurons ventrolateral to the rostral Bötzinger complex (4,8,14,17). Supposedly, the pre-BötzC rhythm generator is normally dominant, and it inhibits the rostral pre-I neurons (14), which initiate rhythmic abdominal muscle contraction when preBötzC inspiratory neuronal activity is depressed (4, 8).…”

“…Recently, it has been proposed that, within the medulla, there are two respiratory rhythm generators, which are mutually inhibitory and each capable of generating a rhythm under different conditions: one is an inspiratory generator composed of pre-BötzC inspiratory neurons, and the second is an expiratory generator composed of preinspiratory (pre-I) neurons ventrolateral to the rostral Bötzinger complex (4,8,14,17). Supposedly, the pre-BötzC rhythm generator is normally dominant, and it inhibits the rostral pre-I neurons (14), which initiate rhythmic abdominal muscle contraction when preBötzC inspiratory neuronal activity is depressed (4,8).…”

“…Supposedly, the pre-BötzC rhythm generator is normally dominant, and it inhibits the rostral pre-I neurons (14), which initiate rhythmic abdominal muscle contraction when preBötzC inspiratory neuronal activity is depressed (4,8).…”

Effect of hypothermia on respiratory rhythm generation in hamster brainstem–spinal cord preparations

“…Since the cold tolerance of neonatal hamsters in vivo is greater than the cold tolerance of neonatal rats (Adolph, 1951) and is not lost to the same extent in adults, we predicted that hamster brainstem-spinal cord preparations would be more cold tolerant than rat brainstem-spinal cord preparations and would also be able to autoresuscitate. Furthermore, episodic patterns of respiratory motor discharge have recently been described in neonates and are suggested to be a consequence of pharmacological blockade of multiple rhythm generators underlying respiratory rhythm (Mellen et al, 2003) and fractionated breaths and episodic breathing have been seen in in vitro neonatal rat brainstem preparations at lower temperatures (Mellen et al, 2002). Since hibernators in vivo exhibit episodic breathing as adults, both during hibernation at reduced temperature (body temperature = 5-20 • C) (Zimmer and Milsom, 2000) and during severe hypothermia (body temperature = 5-10 • C) (Zimmer and Milsom, 2002), the production of episodic breathing at low temperatures may be a characteristic retained from birth in these species, just as cold tolerance appears to be.…”