Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy-

Authors
D. Balayssac, A. Cayre, B. Ling, J. Maublant, F. Penault-Llorca et al.

Lab
INSERM U766, Faculté de Médecine et de Pharmacie, CHU Clermont-Ferrand, Clermont Université, Université d’Auvergne, Clermont-Ferrand, France.

Journal
Neuroscience Letters

Abstract
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.

BIOSEB Instruments Used:
Rodent pincher - analgesia meter (BIO-RP-M)