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  • Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia.

Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia.

Life sciences (2015-03-10)
Satoko Kimura, Yoshiaki Ohi, Akira Haji
ABSTRACT

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. 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. 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. Inhibition of PDE4 may be a possible approach for overcoming morphine-induced ventilatory depression without loss of analgesia.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Caffeine, SAJ special grade, ≥98.5%
Sigma-Aldrich
Urethane, ≥99.0% (GC)
Sigma-Aldrich
Caffeine, meets USP testing specifications, anhydrous
Sigma-Aldrich
Caffeine, Sigma Reference Standard, vial of 250 mg
Sigma-Aldrich
Caffeine, BioXtra
Sigma-Aldrich
Urethane, ≥99%
Sigma-Aldrich
Caffeine, powder, ReagentPlus®
Sigma-Aldrich
Rolipram, solid, ≥98% (HPLC)
Sigma-Aldrich
Caffeine, anhydrous, 99%, FCC, FG