Revisiting tolerance from the endogenous morphine perspective.

Tolerance represents a dynamic mechanism that can be used to temper various regulatory processes regardless of whether they mediate excitation or inhibition. Tolerance operationally directs state-dependent attenuation of the action of endogenous and exogenous morphine. For example, tolerance ensures that immuno-inhibition induced by morphine does not compromise a requisite functional system over an extended period of time. In the nervous system, tolerance to inhibitory action insures that excitatory tone is resumed. Thus, desensitization sets in and allows various essential processes to be operational once again. Clearly, the temporal rebound of diverse immune and nervous processes involved with opiate actions provides a self-contained operational mechanism to ensure survival of the organism. Furthermore, love and/or pleasure, and satiety, are complex neurobiological phenomena linked to limbic brain reward circuitry. These processes are critically dependent on oxytocin, vasopressin, dopamine, endogenous morphine and serotoninergic signaling. Naturally rewarding and/or pleasurable activities are usually governed by beneficial biological behaviors like eating, sex, and reproduction. It is our contention that critically important tolerance mechanisms extend to behaviors mediated by CNS reward systems. In other words, we become satisfied with sex, food, pleasure for the moment and disinterest creeps in until the "urges" return.