cAMP‐dependent reversal of opioid‐ and prostaglandin‐mediated depression of the isolated respiratory network in newborn rats

Abstract

Membrane potential (Vm) and resistance (Rm) of ventral respiratory group (VRG) neurons were measured in the isolated brainstem–spinal cord from newborn rats during bath application of the opioid receptor agonists fentanyl or [D‐Ala2, D‐Leu5]‐enkephalin (Ala‐Leu‐Enk) and of the prostaglandin Et (PGE1). PGE1 (0.1–3 μm) and fentanyl or Ala‐Leu‐Enk (1–50 μm) produced depression and, at higher doses, block of inspiratory nerve activity and respiration‐related postsynaptic potentials. This apnoea was associated with hyperpolarization and Rm fall in 25% of thirty‐two VRG neurons tested, whereas resting Vm and Rm were not changed in the other cells. The selective μ‐ and δ‐receptor blockers naloxonazine (10–20 μm) and naltrindole (50–100 μM) antagonized the effects of 5 μm fentanyl and 50 μM Ala‐Leu‐Enk, respectively. Opioid‐ and PGE1‐evoked respiratory depression was reversed upon elevation of endogenous cAMP levels by stimulating adenylyl cyclase with 100 μM forskolin, activating dopamine D1 receptors with 50–100 μm 6‐chloro‐7,8‐dihydroxy‐3‐allyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine (6‐chloro‐APB) or preventing cAMP breakdown with 50–100 μm isobutylmethylxanthine. The results indicate that opioid‐ or prostaglandin‐induced respiratory depression is due to a fall in cAMP levels in cells responsible for generation of rhythm or providing a tonic drive to the respiratory network. We suggest that elevation of cAMP levels is an effective antidote in neonates against such forms of respiratory depression.

In hamsters the D1 receptor antagonist SCH23390 depresses ventilation during hypoxia

“…For example D 1 receptors cause excitation by decreasing gamma aminobutyric acid (GABA A ) currents in striatal neurons and cortex and glutamatergic signaling in striatal neurons [14,48]. In the ventral respiratory group neurons application of D 1 agonists stimulated neurons by elevating intracellular levels of cyclic AMP and countered effects of fentanyl [4]. In contrast, in the rat parabrachial nucleus dopamine attenuated the non-NMDA receptor evoked excitatory postsynaptic potentials [10].…”

5-Hydroxytryptamine 1A/7 and 4α Receptors Differentially Prevent Opioid-Induced Inhibition of Brain Stem Cardiorespiratory Function

“…This preventive effect is likely via competition of intracellular signaling pathways. It is possible that stimulation of the -opioid receptors decreases cAMP in GABAergic synaptic terminals, as well as inspiratory neurons, 31 and consequently decreases GABAergic neurotransmission to CVNs and inspiratory drive, whereas stimulation of the 5-HT 4␣ receptors would be predicted to increase cAMP and, thus, increase and restore GABAergic neurotransmission to CVNs and inspiratory drive. …”

Administration of phosphodiesterase inhibitors and an adenosine A1 receptor antagonist induces phrenic nerve recovery in high cervical spinal cord injured rats

“…Following spinal cord injury, administration of cAMP analogs as well as pharmacological agents capable of elevating cAMP levels in neurons have been shown to promote regeneration and functional recovery (Pearse et al 2004;Nikulina et al 2004;Qiu et al 2002a). Furthermore, increased cAMP levels have been associated with improvements in many neural functions including respiration (Ruangkittisakul and Ballanyi, 2006;Ballanyi et al, 1997). Therefore, it is reasonable to hypothesize that theophylline-induced respiratory plasticity in C2 hemisected rats leading to the persistent recovery of the ipsilateral hemidiaphragm may be mediated by the drug's non-selective inhibition of phosphodiesterase enzymes and/or by the blockade of adenosine A1 receptors, both of which can modulate cAMP levels (Beavo et al 1994;Dryden et al 1988).…”