Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy.
Pain from anticancer drugs-induced neuropathies is difficult to treat and can significantly alter the patient's quality of life. These neuropathies are considered relatively resistant to conventional analgesic drugs (opioids). Opioids are also P-glycoprotein substrates and it has been demonstrated that the P-glycoprotein is linked to the integrity of blood-brain barrier protecting the nervous system. Previous works presented an increase of P-glycoprotein in vincristine- and cisplatin-induced neuropathy which could potentially decrease opioid efficiency. To test this hypothesis, the efflux inhibition of P-glycoprotein and the antinociceptive effect of morphine were assessed in normal and cisplatin-induced neuropathic rats after the administration of the P-glycoprotein inhibitor (R101933). R101933 (20 mg/kg) inhibited significantly the efflux transporter under the condition of the study and had no analgesic effect. Nociceptive thresholds were measured by the paw pressure test. R101933 (20 mg/kg) enhanced antinociceptive activity of morphine (0.5 mg/kg) to a maximum of +58% and +35%, respectively compared with control animals and animals treated by morphine alone (0.5 mg/kg). R101933 increased morphine (2 mg/kg) antinociceptive activity to a maximum of +105% compared with control animals and to a maximum of +41% compared with morphine alone (2 mg/kg). This study demonstrated that cisplatin-induced neuropathy may present a particular pathophysiology with a multidrug resistance, of the central nervous system, to analgesics. This resistance can be blocked by a P-glycoprotein inhibitor which may enhance analgesia of low doses of morphine.
Balayssac
David
D
INSERM U766, Faculté de Médecine et de Pharmacie, F-63000 Clermont-Ferrand, France. dbalayssac@chu-clermontferrand.fr
Cayre
Anne
A
Ling
Bing
B
Maublant
Jean
J
Penault-Llorca
Frédérique
F
Eschalier
Alain
A
Coudoré
François
F
Authier
Nicolas
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin; D004357:Drug Synergism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D011312:Pressure; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D017256:Technetium Tc 99m Sestamibi
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D001552:Benzazepines; D011804:Quinolines; D009020:Morphine; D017256:Technetium Tc 99m Sestamibi; C411474:laniquidar; D002945:Cisplatin