Intracellular signaling mechanisms underlying the
opioid system regulation of nociception,
neurotransmitters release, stress responses, depression, and the modulation of reward circuitry have been investigated from different points of view. The presence of the
ubiquitin proteasome system (UPS) in the synaptic terminations suggest a potential role of
ubiquitin-dependent mechanisms in the control of the membrane occupancy by
G protein-coupled receptors (GPCRs), including those belonging to the
opioid family. In this review, we focused our attention on the role played by the ubiquitination processes and by UPS in the modulation of
opioid receptor signaling and in pathological conditions involving the endogenous
opioid system. The collective evidence here reported highlights the potential usefulness of
proteasome inhibitors in
neuropathic pain, addictive behavior, and
analgesia since these molecules can reduce
pain behavioral signs,
heroin self-administration, and the development of
morphine analgesic tolerance. Moreover, the complex mechanisms involved in the effects induced by
opioid agonists binding to their receptors include the ubiquitination process as a post-translational modification which plays a relevant role in receptor trafficking and degradation. Hence, UPS modulation may offer novel opportunities to control the balance between therapeutic versus adverse effects evoked by
opioid receptor activation, thus, representing a promising druggable target.