Neuraminidase inhibitor, oseltamivir blocks GM1 ganglioside-regulated excitatory opioid receptor-mediated hyperalgesia, enhances opioid analgesia and attenuates tolerance in mice.
The endogenous glycolipid GM1 ganglioside plays a critical role in nociceptive neurons in regulating opioid receptor excitatory signaling demonstrated to mediate "paradoxical" morphine hyperalgesia and to contribute to opioid tolerance/dependence. Neuraminidase (sialidase) increases levels of GM1, a monosialoganglioside, in these neurons by enzymatic removal of sialic acid from abundant polysialylated gangliosides. In this study, acute treatment of mice with the neuraminidase inhibitor, oseltamivir enhanced morphine analgesia. Acute oseltamivir also reversed "paradoxical" hyperalgesia induced by an extremely low dose of morphine, unmasking potent analgesia. In chronic studies, co-administration of oseltamivir with morphine prevented and reversed the hyperalgesia associated with morphine tolerance. These results provide the first evidence indicating that treatment with a neuraminidase inhibitor, oseltamivir, blocks morphine's hyperalgesic effects by decreasing neuronal levels of GM1. The present study further implicates GM1 in modulating morphine analgesia and tolerance, via its effects on the underlying excitatory signaling of Gs-coupled opioid receptors. Finally, this work suggests a remarkable, previously unrecognized effect of oseltamivir-which is widely used clinically as an antiviral agent against influenza-on glycolipid regulation of opioid excitability functions in nociceptive neurons.
Crain
Stanley M
SM
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Ave., Bronx, NY 10461, USA. smcrain@aecom.yu.edu
Shen
Ke Fei
KF
D000081:Acetamides / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005677:G(M1) Ganglioside / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D053139:Oseltamivir; D010147:Pain Measurement; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D000081:Acetamides; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D011957:Receptors, Opioid; D053139:Oseltamivir; D005677:G(M1) Ganglioside; D009020:Morphine; D009439:Neuraminidase