The repeated administration of opiate drugs such as morphine results in the development of tolerance to their analgesic, rewarding (euphoric) and respiratory-depressant effects; thus, to obtain the same level of response with subsequent administrations, a greater dose must be used. Tolerance can limit the clinical efficacy of opiate drugs and enhance the social problems that are inherent in recreational opioid abuse. Surprisingly, the mechanism (or mechanisms) underlying the development of morphine tolerance remains controversial. Here, we propose that protein kinase C could have a crucial role in the desensitization of μ-opioid receptors by morphine and that this cellular process could contribute to the development and maintenance of morphine tolerance in vivo.
Bailey, C. P., Smith, F. L., Kelly, E., Dewey, W. L., & Henderson, G. (2006). How important is protein kinase C in μ-opioid receptor desensitization and morphine tolerance? Trends in Pharmacological Sciences, 27(11), 558-565. https://doi.org/10.1016/j.tips.2006.09.006