AAH8 may be a better alternative than traditional opioid analgesics, producing antinociception with less development of tolerance and dependence and may be less rewarding than morphine.

Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

ID 18014 Poster Board 210Opioid therapeutics, such as morphine, that act at the mu-opioid receptor (MOR) are the clinical standard for managing pain. Although opioids are effective, their use leads to severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for safer alternatives to manage pain. One promising approach is to enhance the effects of the endogenous opioid system by the use of positive allosteric modulators (PAMs) of MOR. A known PAM, BMS-986122, enhances MOR agonist potency in cellular models. In mouse models, BMS-986122 promotes the antinociceptive activity of endogenous opioid peptides and exogenous opioid drugs in various pain assays. Moreover, at an effective antinociceptive dose in mice, BMS-986122 produces less severe adverse effects than morphine, as determined by measures of constipation, respiratory depression, and conditioned place preference. However, we do not yet know if the side effects of traditional exogenous opioids are increased by PAM modulation. Here we compare the ability of BMS-986122 to enhance the action of three structurally diverse opioid therapeutics, morphine, methadone, and fentanyl. We find that BMS-986122 increases the antinociceptive effects of the drugs in the warm water tail withdrawal and hot plate assays without promoting constipation, respiratory depression, or reward in CD1 male and female mice. Future work will assess the effects of BMS-986122 in chronic pain models. If BMS-986122 enhances MOR-mediated antinociception but not MOR-mediated adverse effects, the development of PAMs as standalone pain medications and opioid-sparing drugs will be a valuable approach to effective pain management.

Opioid therapeutics, such as morphine, that act at the mu‐opioid receptor (MOR) are the clinical standard for patients struggling to manage symptoms associated with pain. It is widely understood that although opioids are effective at treating pain, their use leads to the development of severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for a safer alternative to manage pain. One such alternative is to enhance the effects of the body’s endogenous opioid system by positive allosteric modulation (PAM) of MOR. A known PAM, BMS‐986122, enhances MOR agonist potency in cellular models and MOR agonist mediated antinociception in vivo. In addition, this PAM is active alone in a variety of mouse pain assays by promoting the activity of endogenous opioid peptides. Moreover, at an effective antinociceptive dose, BMS‐986122 alone produces less severe adverse effects than morphine as determined by measures of constipation, respiratory depression, and conditioned place preference. However, we do not yet know how the overall pharmacology of opioids is affected by PAMs or if all opioid drugs are equally sensitive to PAM modulation. Here we compare the ability of BMS‐986122 to enhance the action of three structurally diverse opioid drugs, morphine, methadone, and fentanyl, in an acute pain assay and in an assay examining respiratory depression using CD‐1 male and female mice. We show that BMS‐986122 increases the antinociceptive effects of the opioid therapeutics in the warm water tail withdrawal assay without promoting the ability of the drugs to lower blood oxygen levels or heart rate. Future work will assess the effects of BMS‐986122 in additional acute and chronic pain models and with a more diverse group of opioids. If additional experiments support the concept that BMS‐986122 enhances MOR‐mediated antinociception but not MOR‐mediated respiratory depression, this will validate the development of MOR‐PAMs as standalone pain medications and support the use of PAMs as opioid‐sparing drugs for the effective management of pain.