Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

Abstract

Lalley, Peter M. Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons. Am J Physiol Regul Integr Comp Physiol 290: R1387-R1396, 2006. First published November 10, 2005 doi:10.1152/ajpregu.00530.2005.-Opiates have effects on respiratory neurons that depress tidal volume and air exchange, reduce chest wall compliance, and slow rhythm. The most dose-sensitive opioid effect is slowing of the respiratory rhythm through mechanisms that have not been thoroughly investigated. An in vivo dose-response analysis was performed on medullary respiratory neurons of adult cats to investigate two untested hypotheses related to mechanisms of opioid-mediated rhythm slowing: 1) Opiates suppress intrinsic conductances that limit discharge duration in medullary inspiratory and expiratory neurons, and 2) opiates delay the onset and lengthen the duration of discharges postsynaptically in phase-regulating postinspiratory and late-inspiratory neurons. In anesthetized and unanesthetized decerebrate cats, a threshold dose (3 g/kg) of the -opioid receptor agonist fentanyl slowed respiratory rhythm by prolonging discharges of inspiratory and expiratory bulbospinal neurons. Additional doses (2-4 g/kg) of fentanyl also lengthened the interburst silent periods in each type of neuron and delayed the rate of membrane depolarization to firing threshold without altering synaptic drive potential amplitude, input resistance, peak action potential frequency, action potential shape, or afterhyperpolarization. Fentanyl also prolonged discharges of postinspiratory and late-inspiratory neurons in doses that slowed the rhythm of inspiratory and expiratory neurons without altering peak membrane depolarization and hyperpolarization, input resistance, or action potential properties. The temporal changes evoked in the tested neurons can explain the slowing of network respiratory rhythm, but the lack of significant, direct opioid-mediated membrane effects suggests that actions emanating from other types of upstream bulbar respiratory neurons account for rhythm slowing.fentanyl; medullary respiratory neurons; phrenic nerve activity; naloxonazine; naltrindole OPIATES ARE WELL KNOWN for their ability to depress ventilation by slowing breathing frequency and reducing tidal volume, gas exchange, upper airway patency, and chest wall compliance (3,4,36,39). They also blunt respiratory network responsiveness to hypoxia and CO 2 /acidosis (11,25,51,60).Opiate slowing of respiratory rhythm, leading to arrest of breathing after the highest doses, has been the topic of many experimental investigations (2,10,14,16,22,24,30,34,37,48,52,60). According to most recent studies, rhythm slowing seems to be principally related to depression of inspiratory interneurons in the pre-Bötzinger complex (PBC) (15, 34, 37), a region within the ventrolateral respiratory column (VRC) that seems to be critical for generation of respiratory rhythm (40, 52). However, endogenous opioid peptides are distributed throughout the bulbar respiratory ...

Opioid Receptors on Bulbospinal Respiratory Neurons Are Not Activated During Neuronal Depression by Clinically Relevant Opioid Concentrations

“…Our finding that clinically relevant concentrations, which are in the nanomolar range, have no direct effect on respiratory premotor neurons is consistent with those of Lalley (2006), who used intracellular recordings from ventrolateral respiratory column neurons in barbiturate-anesthetized or decerebrate adult cats. Intravenous doses of the agonist fentanyl in the clinical dose range (3-7 g/kg) led to significant slowing of the respiratory rhythm as well as an increase in duration of discharge in inspiratory and expiratory bulbospinal and propriobulbar neurons.…”

“…However, there were no changes in the intrinsic properties of the studied neurons; that is, there was no evidence from measurements of input resistance or action potential threshold, shape, and afterhyperpolarization that the doses of fentanyl that slowed rhythm acted on membrane conductances. Lalley (2006) suggested that slowing was evidently generated through effects on other neurons that control the onset and termination of inspiratory and expiratory neuron discharges, such as those in the pons and pre-Bötzinger complex.…”

Serotonin targets inhibitory synapses to induce modulation of network functions

“…The latter are well-known pharmacological targets for anaesthesia and the treatment of pain. Clinically useful m-OR agonists, however, depress central respiratory activity, causing cessation of rhythmic breathing movements (Mellen et al 2003;Lalley 2006). An averting medical approach against opioidinduced apnoea is possible with 5-HT 4 R agonists that re-activate cellular AC (Manzke et al 2003), but such medication is so far not useful in men because ) to anaesthetized rats in vivo increased rRMA (red trace).…”

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

“…In addition to measurement limitations, pharmacokinetics and pharmacodynamics seem to differ significantly between species for both intravenous anesthetics and opioids and seem subject to allometry (378). As a result, rodents (rats and mice) and other small mammals (rabbits) require much larger single doses (mg/kg) and infusion rates (mg/kg/h) of intravenous agents (61,482,491) and opioids (microgram/kg) (25,117,314,359,361,436,772,774) on a weight basis than larger mammals (dogs) and primates (humans). Finally, it is important to realize that only the free plasma concentrations in the aqueous phase of intravenous anesthetics or opioids seem to be relevant for the clinical effect, not the total plasma concentration.…”

“…Both morphine and the more powerful synthetic opioids of the phenylpiperidine class (fentanyl, alfentanil, sufentanil, and remifentanil) lead to dose-dependent respiratory depression. At perioperative analgesic doses for humans (morphine 0.1-0.2 mg/kg, fentanyl 0.5-1 μg/kg, see Tables 2 and 6), which result in effect site concentrations in the low nanomolar range (see Table 6), the first sign of clinically relevant respiratory depression is a slowing in respiratory rate, which at higher doses of the synthetic fentanyl analogues (fentanyl > 3 μg/kg) will lead to apnea (359,361,362). Depression of tidal volume (TV) secondary to depression of the central chemoreflex and depression of excitatory drive from the brainstem to the inspiratory motoneurons is also apparent at analgesic doses but this often remains clinically unrecognized in spontaneously breathing subjects, because the hypoventilation leads to accumulation of PaCO 2 with a resultant increase in chemodrive and thus TV.…”