Satoko Kimura1, Yoshiaki Ohi1, Akira Haji2. 1. Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan. 2. Laboratory of Neuropharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan. Electronic address: haji@dpc.agu.ac.jp.
Abstract
AIMS: 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. MAIN 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. KEY FINDINGS: 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. SIGNIFICANCE: Inhibition of PDE4 may be a possible approach for overcoming morphine-induced ventilatory depression without loss of analgesia.
AIMS: 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. MAIN 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. KEY FINDINGS: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. SIGNIFICANCE: Inhibition of PDE4 may be a possible approach for overcoming morphine-induced ventilatory depression without loss of analgesia.
Authors: Jan-Marino Ramirez; Nicholas J Burgraff; Aguan D Wei; Nathan A Baertsch; Adrienn G Varga; Helen A Baghdoyan; Ralph Lydic; Kendall F Morris; Donald C Bolser; Erica S Levitt Journal: J Neurophysiol Date: 2021-04-07 Impact factor: 2.714
Authors: Paulina M Getsy; Santhosh M Baby; Walter J May; James N Bates; Christopher R Ellis; Michael G Feasel; Christopher G Wilson; Tristan H J Lewis; Benjamin Gaston; Yee-Hsee Hsieh; Stephen J Lewis Journal: Front Pharmacol Date: 2022-09-28 Impact factor: 5.988