Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia.
OBJECTIVE
Ventilatory disturbance is a fatal side-effect of opioid analgesics. Separation of analgesia from ventilatory depression is important for therapeutic use of opioids. It has been suggested that opioid-induced ventilatory depression results from a decrease in adenosine 3',5'-cyclic monophosphate content in the respiratory-related neurons. Therefore, we examined the effects of caffeine, a methylxanthine non-selective phosphodiesterase (PDE) inhibitor with adenosine antagonistic activity, and rolipram, a racetam selective PDE4 inhibitor, on ventilatory depression induced by morphine.


METHODS
Spontaneous ventilation and paw withdrawal responses to nociceptive thermal stimulation were measured in anesthetized rats simultaneously. The efferent discharge of the phrenic nerve was recorded in anesthetized, vagotomized, paralyzed and artificially ventilated rats.


RESULTS
Rolipram (0.1 and 0.3 mg/kg, i.v.) and caffeine (3.0 and 10.0 mg/kg, i.v.) relieved morphine (1.0 mg/kg, i.v.)-induced ventilatory depression but had no discernible effect on its analgesic action. Rolipram (0.3 and 1.0 mg/kg, i.v.) and caffeine (10.0 and 20.0 mg/kg, i.v.) recovered morphine (3.0 mg/kg, i.v.)-induced prolongation and flattening of inspiratory discharge in the phrenic nerve.


CONCLUSIONS
Inhibition of PDE4 may be a possible approach for overcoming morphine-induced ventilatory depression without loss of analgesia.
Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
Satoko
S
Kimura
Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
Yoshiaki
Y
Ohi
Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan. Electronic address: haji@dpc.agu.ac.jp.
Akira
A
Haji
D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology* / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010791:Phrenic Nerve / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012120:Respiration Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D015656:Respiratory Mechanics / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology; D014628:Vagotomy
D000701:Analgesics, Opioid; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D002110:Caffeine; D009020:Morphine; D020889:Rolipram
Caffeine; Paw immersion test; Phosphodiesterase 4; Phrenic nerve discharge; Rolipram; Spontaneous breathing