CHAPTER 9: Positive Allosteric Modulators of Opioid Receptors Check Access

Activation of opioid receptors produces powerful analgesia; and µ-opioid receptor agonists such as morphine and oxycodone remain the “gold standard” for pain therapy, despite their abuse liability and dangerous side effect profile. Safer pain medications are urgently needed. The recent discovery of positive allosteric modulators (PAMs) of µ- and δ-opioid receptors provides a new approach for exploiting the analgesic effects of opioid receptor activation. PAMs enhance endogenous opioid signaling but do not activate the receptor directly, and therefore may be expected to exert analgesic effects while improving upon the side effect profile and abuse liability associated with direct-acting opioid agonists. The discovery and characterization of the first opioid PAM molecules is described, as well as the rationale for the development of opioid PAMs as novel therapeutic agents for the treatment of pain.