Promising Strategies for Solving the Opioid Crisis

The development of addiction-free medications effective for treating severe pain is a major aim for combating the misuse of prescription opioids, preventing the development of opioid addiction, and avoiding the misfortune of an overdose. Although widely used μ-opioid receptor agonists (oxycodone, hydrocodone, and morphine) are extremely effective analgesics in a clinical setting, they have helped fuel the opioid crisis, by carrying both a high abuse liability and high risk for causing respiratory arrest. Non-opioid treatments currently available for acute pain related to tissue damage and inflammation include prescription and over-the-counter acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs; non-selective COX inhibitors such as ibuprofen, aspirin, and naproxen), and corticosteroids. Non-opioid treatments for persistent pain related to nerve damage have explored the use of FDA-approved anti-epileptic drugs (gabapentin, topiramate, and divalproex), tricyclic antidepressants (imipramine, nortriptyline, amitriptyline, and doxepin), and serotonin-norepinephrine reuptake inhibitors (venlafaxine and duloxetine). In a continued effort to create safe and more effective opioid alternatives, several novel strategies are also being employed.

Mixed Opioid Receptor Agonism/Antagonism

Of the four opioid receptor types—μ-, κ-, δ-opioid receptors, and the nociceptin (NOP)/orphanin FQ/opioid receptor-like orphan receptor—the μ-opioid receptor has been most extensively studied due to its role in mediating the actions of morphine-type analgesic agents as well as drugs of abuse. Various approaches to the development of analgesic drugs have explored unique receptor agonism and/or antagonism combinations or mixed agonism/antagonism of the various opioid receptor types. For example, δ-agonists such as SNC 80 can enhance the analgesic potency and efficacy of μ-agonists. The analgesic pentazocine functions as a μ-partial agonist and κ-full agonist. Furthermore, δ- or κ-antagonists may reduce or even prevent the development of tolerance and physical dependence by μ-agonists. For instance, buprenorphine, which is used to counter opiate addiction, displays antagonist behavior at the κ-receptor. It also tightly binds the μ-receptor exhibiting partial agonist behavior that is highly competitive against the binding of other opioids. Incomplete dissociation of buprenorphine from the μ-receptor prolongs this activity. Though κ- and δ-opioid receptor ligands can show efficacy as analgesics, they often display narrow therapeutic windows and can present adverse side effects, such as dysphoria and convulsions. Many also carry high potential for misuse due to their reinforcing effects. Because of this, different combinations of opioid receptor agonists/antagonists continue to be developed.

Most recently, the dual μ-opioid/nociceptin receptor partial agonist AT-121 has shown promise by relieving pain in non-human primates through μ-opioid receptor stimulation while simultaneously blocking its addictive actions via the nociceptin receptor (Figure 1).¹ Agonists targeting nociceptin receptors have been shown to enhance the analgesic activity of μ-opioid receptor agonists while downplaying their addictive properties. Furthermore, nociceptin receptor agonists do not produce respiratory depression or reinforcing effects. As a partial agonist at both receptors, AT-121 is effective at 100-fold lower concentrations than a typical morphine dose and appears devoid of the side effects that other opioids typically induce, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence.¹ Though more work is needed to bring this into clinical applications, bifunctional μ-receptor/nociceptin partial agonists have potential to replace current opioid therapies by offering a broader therapeutic window.

Figure 1. Dynamic interchange between the μ-opioid and nociceptin receptors when activated by AT-121.

Adenylyl Cyclase 1 Inhibition

When activated, opioid receptors that are coupled to inhibitory G-proteins decrease adenyl cyclase-mediated production of the second messenger cyclic AMP (Figure 2). Additionally, voltage-gated calcium channels are inhibited, producing a decrease in calcium influx, and potassium channels are activated, which leads to hyperpolarization. The hyperpolarized state causes inhibition of neuronal signaling, which in the case of pain, inhibits transmission of the pain signal. Prolonged activation of opioid receptors, however, causes the adaptive sensitization and superactivation of adenyl cyclase and leads to opioid dependence.

Figure 2. Signaling through the G protein-linked opioid receptor decreases adenylyl cyclase and calcium influx while increasing potassium efflux, which leads to inhibition of the pain signal.

Adenylyl cyclases (ACs) can be divided into four groups: 1) those activated by calcium/calmodulin (AC1, AC3, AC8); 2) those conditionally activated by Gβγ subunits (AC2, AC4, AC7); 3) those inhibited by calcium (AC5, AC6); and 4) those insensitive to the AC activator forskolin (AC9). Studies with AC1 knockout mice suggest that selective inhibition of AC1 may be useful for treating chronic and inflammatory pain while avoiding opioid dependence.

Chronic pain develops through a learned association to a stimulus. This association is strengthened through long-term potentiation (LTP), and AC1 activation generates the cyclic AMP required for LTP. The analgesic properties associated with AC1 inhibition, thus, are linked to a decrease in cyclic AMP production. The AC1-selective inhibitor ST034307 has been shown to dose-dependently prevent opioid receptor-mediated sensitization of AC1 and to exert analgesic effects in a mouse model of pain.² Specificity for inhibition of AC1 in the treatment of pain is crucial since inhibition of other ACs are linked to memory impairment or muscle growth. The development of future AC1 inhibitors for use either alone or in combination with opioids may reduce the amount of opioid required to achieve pain relief and prevent the adaptive changes associated with opioid dependence.

DAGL or MAGL Inhibition

Diacylglycerol lipases (DAGLs) hydrolyze sn-1 fatty acids from diacylglycerols to produce 2-arachidonyl glycerol (2-AG) (Figure 3), an endocannabinoid that controls inflammation and acts as a cannabinoid receptor agonist. Monoacylglycerol lipase (MAGL) hydrolyzes 2-AG to arachidonic acid and glycerol, thus terminating its biological function (Figure 3). Highly selective MAGL inhibitors such as JZL 184 have been shown to elevate brain 2-AG levels, lower pro-inflammatory prostaglandins, and elicit analgesic activity that qualitatively mimics direct central cannabinoid agonists. However, in mice chronically treated with MAGL inhibitors, these cannabinoid receptor-mediated antinociceptive effects can diminish and show cross tolerance to cannabinoid receptor agonists. Physical dependence can also develop as cannabinoid receptors become desensitized to prolonged and heightened 2-AG levels.

Figure 3. Pro-inflammatory mediators are generated downstream of the DAGL-mediated production of 2-AG.

Because of its role in regulating 2-AG and downstream arachidonic acid-derived pro-inflammatory signaling molecules, DAGL inhibitors have become another possible new drug target for reducing pain. Of the two known isoforms, DAGLβ enriched in macrophages and microglia seems the most promising focus since long-term disruptions of CNS-associated DAGLα result in behavioral defects and seizures. Selective inhibitors of DAGLβ, such as KT109 and KT172 and the more potent isomer (R)-KT109, have been shown to reduce inflammation, similar to aspirin and NSAIDs.³ However, unlike NSAIDs, DAGLβ inhibitors can provide pain relief in preclinical models without gastrointestinal toxicity when used long term.³ And, in contrast to opioids, DAGLβ inhibitors do not exhibit addictive properties. Moreover, DAGLβ inhibitors stop inflammation without impacting the normal immune response, which is another complication seen with long-term use of NSAIDs.⁴ Thus, DAGLβ inhibitors represent a new route to treating long-term inflammation and pain without the side effects of toxicity, risk of addiction, or immune system compromise observed with some other current treatment options.

sEH Inhibition

Soluble epoxide hydrolase (sEH) is being targeted for the control of both inflammatory and neuropathic pain due to its ability to rapidly metabolize epoxidized fatty acids that have analgesic and anti-inflammatory actions. Epoxy fatty acids are formed by the action of cytochrome P450 enzymes on arachidonic acid and other long-chain polyunsaturated fatty acids (PUFAs) (Figure 4). A number of regioisomers are formed by the epoxidation of any one of the double bonds of the PUFA. Epoxy fatty acids block the adherence and infiltration of activated monocytes by inhibiting ICAM-1, E-selectin, and VCAM-1 expression in endothelial cells. They can also block nuclear translocation of NF-κB and the phosphorylation of IκBα, which activates NF-κB signaling. Several enzymes involved in inflammation are also downregulated including COX-2, which limits the production of prostaglandin E₂, while anti-inflammatory transcription factors such as STAT3 and PPARs can be activated. There is also evidence that epoxy fatty acids bind to the transient receptor potential (TRP) family of ligand-gated ion channels, which are critical detectors and transducers of pain-causing stimuli.

Figure 4. Epoxy fatty acids block inflammation through multiple pathways resulting in the reduction of inflammatory mediators and the prevention of neutrophil recruitment.

As a strategy to avoid the adverse or addictive effects of opioids, inhibition of sEH would sustain the pain- and inflammation-resolving activity of fatty acid epoxides. Potent sEH inhibitors, including AUDA, the 1-aryl-3-(1-acylpiperidin-4-yl)urea analog CAY10640, trans-AUCB, and TPPU, have been shown to reduce hyperalgesia in animal pain models.⁵ Additionally, phase 1 clinical trials of an FDA-approved sEH inhibitor are underway to investigate the efficacy of EC5026 (BPN-19186) in the treatment of pain.

Cayman Offers a Select Group of Tools to Study Pain

These novel compounds along with more classic antinociceptive compounds and various additional tools are available in Cayman’s catalog to help you probe the pharmacology of the pain signaling pathway to address the need for better treatments for pain relief.

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References

1. Ding, H., Kiguchi, N., Yasuda, D., et al. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci. Transl. Med. 10(456), eaar3483 (2018).

2. Brust, T.F., Alongkronrusmee, D., Soto-Velasquez, M., et al. Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties. Sci. Signal.10(467), 1678-1692 (2017).

3. Wilkerson, J.L., Ghosh, S., Bagdas, D., et al. Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. Br. J. Pharmacol.173(10), 1678–1692 (2016).

4. Shin, M., Buckner, A., Prince, J., et al. Diacylglycerol lipase-β Is required for TNF-α response but not CD8+ T cell priming capacity of dendritic cells. Cell Chem. Biol. 26, 1-6 (2019).

5. Wagner, K.M., McReynolds, C.B., Schmidt, W.K., et al. Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol. Ther. 180, 62-76 (2017).