Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins.
Opioid receptors belong to the G protein-coupled receptor (GPCR) family, the largest family of membrane proteins in the human genome. Based on molecular cloning and pharmacological studies, three types of opioid receptors have been characterized: the μ-opioid receptor (MOR), the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR). Opioid receptors are expressed in the peripheral nervous system on pre- and post-synaptic sites in the spinal cord dorsal horn and on primary afferent neurons, as well as in the brain. The primary physiological function of the opioid receptors is the modulation of pain sensation. Alleviation of pain (analgesia) is achieved through activation of opioid receptors by binding of either endogenous or exogenous opioid agonists. Opioid receptors are differentially regulated by agonist and antagonist treatment. For example, chronic treatment with opioid agonists results in tolerance that may or may not be associated with changes in opioid receptor density. On the other hand, chronic opioid antagonist exposure can increase opioid agonist potency (functional supersensitivity) and this is usually associated with an increase in opioid receptor density (upregulation). In short, opioid efficacy has been shown to be important in predicating behavioral and biochemical outcomes. Studies suggest that ligands at opioid receptors can display a spectrum of efficacy from positive to negative.
Endogenous opioids (enkephalins, dynorphins, β-endorphin and endomorphins) are neuropeptides synthesized in the body and released under pain conditions such as stress, injury and exercise. Exogenously administered opioid agonists (morphine, levorphanol, oxymorphon, meperidine, oxycodone, fentanyl) represent the best analgesic drugs currently used for the treatment of moderate to severe pain. Regrettably, after prolonged treatment, these drugs produce serious side effects, including physical dependence and tolerance. Therefore, understanding the mechanism of sustained opioidmediated effects is critical for improving the properties of clinically used analgesics by minimizing their undesirable effects.
Upon stimulation, opioid receptors produce their effect by activating the inhibitory Gi/o proteins, and coupling to a number of signaling pathways involving ion channels (GIRK type K+ channels and Ca2+ channels), protein kinases (PKA, PKC, MAPK) and transcription factors (CREB, AP1). This acute signaling is extensively regulated by receptor phosphorylation, desensitization, internalization, degradation and expression. Acute opioid signaling leads to hyperpolarization of the neuron and attenuation of neurotransmitter release, resulting in a decreased pain transmission. On the other hand, prolonged opioid signaling leads to regulatory events, which are thought to contribute to the development of opioid tolerance. Successful long-term pain therapy must therefore consider not only the analgesic effects of a drug but also its adverse effects upon sustained treatment, such as opioid tolerance. The exact cellular mechanisms underlying opioid tolerance, however, are not entirely understood. In addition, while considerable attention has been given to the role of the MOR in pain therapy, much less is known about the involvement of the delta opioid receptors.
Navratilova, E. (2007). Regulation of the human delta opioid receptor (Doctoral dissertation, The University of Arizona).