主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Ethanol has previously been reported to reverse tolerance to morphine-induced respiratory depression in mice (1,2) as well as reversing morphine-induced cellular tolerance in rat locus coeruleus neurones (3). The present investigation examined the role of acetaldehyde, the primary metabolite of ethanol, in ethanol reversal of morphine tolerance.
Respiration (minute volume) was measured by whole body plethysmography in male CD-1 mice. Tolerance to morphine was induced by subcutaneous implantation of a 75 mg morphine pellet or placebo pellet for 6 d. All drugs were administered i.p. Activation of protein kinase C (PKC) was measured in HEK293 cells by sub-cellular fractionation, with activated PKC translocating from the cytosol to the plasma membrane detected by Western blotting.
In naive mice saline or acetaldehyde (50 or 100 mg/kg) caused no significant depression of respiration. In placebo pellet-implanted mice morphine (10 mg/kg) rapidly depressed respiration. In morphine-pellet implanted mice, morphine and acetaldehyde did not significantly depress respiration. However, co-administration of acetaldehyde with morphine produced significant respiratory depression i.e. acetaldehyde had reversed morphine tolerance. Pre-treatment with the acetaldehyde chelator, D-penicillamine (50 mg/kg), for 30 min significantly reduced the ability of ethanol to reverse morphine tolerance. Pre-treatment with the PKC inhibitor calphostin C (45 ug/kg) for 30 min significantly reversed tolerance induced by morphine.
Treatment of HEK293 cells with PMA (100 nM) resulted in translocation of PKC from the cytosol to the plasma membrane. Pre-treatment of HEK293 cells with acetaldehyde (20 mM) for 30-min significantly decreased the translocation of PKC from cytosol to plasma membrane. Pre-treatment with ethanol for 30 min did not alter PKC translocation.
These data provide evidence that acetaldehyde rather than ethanol, reverses tolerance to morphine respiratory depression, an effect likely to be mediated by inhibition of PKC translocation to the plasma membrane.
1. Hill et al, Neuropsychopharm 41(3), 2016
2. Hull et al, J Pharmacol Exp Ther 345(3) 2013
3. Llorente et al, Mol Pharmacol 84:252, 2013
