CAMP-DEPENDENT REVERSAL OF OPIOID-MEDIATED AND PROSTAGLANDIN-MEDIATEDDEPRESSION OF THE ISOLATED RESPIRATORY NETWORK IN NEWBORN RATS

1. Membrane potential (V-m) and resistance (R-m) of ventral respirator y group (VRG) neurons were measured in the isolated brainstem-spinal c ord from newborn rats during bath application of the opioid receptor a gonists fentanyl or [D-Ala(2), D-Leu(5)]-enkephalin (Ala-Leu-Enk) and of the prostaglandin E-1 (PGE(1)). 2. PGE(1) (0.1-3 mu M) and fentanyl or Ala-Leu-Enk (1-50 mu M) produced depression and, at higher doses, block of inspiratory nerve activity and respiration-related postsynapt ic potentials. This apnoea was associated with hyperpolarization and R -m fall in 25 % of thirty-two VRG neurons tested, whereas resting V-m and R-m were not changed in tile other cells. 3. The selective mu- and delta-receptor blockers naloxorazine (10-20 mu M) and naltrindole (50 -100 mu M) antagonized the effects of 5 mu M fentanyl and 50 mu M Ala- Leu-Enk, respectively. 4. Opioid-and PGE(1)-evoked respiratory depress ion was reversed upon elevation of endogenous cAMP levels by stimulati ng adenylyl cyclase with 100 mu M forskolin, activating dopamine D-1 r eceptors with 50-100 mu M allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine (6-chloro-APB) or preventing cAMP breakdown with 50-100 mu M is obutylmethylxanthine. 5. The results indicate that opioid-or prostagla ndin-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. 6. We suggest that elevation of cAMP leve ls is an effective antidote in neonates against such forms of respirat ory depression.