- Email: [email protected]
Pain Wars: A New Hope
Neuron
Spotlight Pain Wars: A New Hope Kyle E. Parker1 and Michael R. Bruchas1,2,* 1Department
of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO, USA for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pain Medicine, Department of Pharmacology, University of Washington, Seattle, WA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.045 2Center
Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics. Today, opioids binding to the mu-opioid receptor (mu) remain the primary analgesics used to treat pain conditions, driving an ever-increasing rate of opioid prescriptions over the last two decades. Unfortunately, long-term therapeutic regimens are complicated by side effects ranging from the milder constipation, vomiting, and nausea, to more severe side effects of respiratory depression, tolerance, physical dependence, and ultimately abuse liability and fatal overdose (Volkow and McLellan, 2016). These complications significantly impact the quality of life of patients and, according to several recent reports, are considered to be a driving force of the current opioid epidemic (National Academies of Sciences, Engineering, and Medicine, 2017). Clearly, the development of innovative therapies that separate opioid analgesia from these detrimental side effects is critical in curtailing this crisis. Understandably, recent scientific efforts are attempting to harness the potent analgesic effects of mu agonism with new strategies to minimize mu agonist-associated side effects. Most of these efforts have focused on the concept of ‘‘biased’’ opioid ligands, which can act via either G-protein or Arrestin-mediated pathways. However, while potentially promising in their own right, some of these ‘‘biased ligand’’ approaches at a single receptor have been revealed to have potential limitations (Austin Zamarripa et al., 2018). As a consequence of some of these limitations, investigators have also sought to re-examine non-selective opioid agonists and develop new bifunctional agonists as emerging basic science research has demonstrated the value of simultaneously targeting multiple opioid recep-
tors within peripheral and central pain and reward systems. Ultimately, these basic insights into the complex functional interactions of pain-modulating systems could also provide a path for devising new strategies in drug development. In recent years, substantial progress has been made in the development of mu and nociceptin opioid peptide (NOP) receptor bifunctional agonists. Mu and NOP share common signaling pathways to Gi-mediated inhibitory networks, and they are also both functionally expressed in pain and reward pathways. In some cases, NOP agonists have been shown to have broader potential for the treatment of neuropathic pain than classical opioids (Schro¨der et al., 2014). Specifically, NOP has been shown to be an encouraging target for the treatment of pain in non-human primates (Ko et al., 2009). Early studies have also indicated the potential of mixed mu/NOP agonists to alleviate side effects of typical mu agonists, including the development of tolerance and dependence. Interestingly, this effect could be due to the chronic desensitization of NOP signaling in reward and tolerance circuits (Lutfy et al., 2001). Additionally, observations from clinically prescribed opioid compounds like buprenorphine have driven a new rationale for the development of bivalent mu/NOP agonists as potential therapeutics in pain management (Zaveri et al., 2013). With their recent publication in Science Translational Medicine, Ding and colleagues sought to test this rationale with the development of a bifunctional mu/NOP agonist, AT-121, and then to thoroughly examine its potential as a non-addictive, analgesic alternative.
1280 Neuron 100, December 19, 2018 ª 2018 Elsevier Inc.
The authors began by developing bifunctional NOP/mu agonists through structure-guided drug design and optimization starting from a NOP-selective chemical scaffold. Following the chemical lead from their NOP ligand library, the authors used rational structure-activity relationship (SAR) optimization with Compound 1, the active-state NOP structure they had previously developed, to synthesize 5 additional analogs with improved NOP binding affinity. The authors then used in vitro pharmacological binding and functional assays to each of the opioid receptor subtypes to establish a rigorous pharmacological profile of each bifunctional agonist. From the data collected with these assays, Analog 5 (AT-121) showed high potency and partial agonist efficacy at both NOP and mu receptors. In comparison to all other analogs, the authors determined AT-121 as the best prototype ligand to explore their hypothesis that a balance between NOP and mu agonist efficacies could be a useful approach to develop new analgesics with reduced side effects. Following the synthesis of AT-121, the authors sought to determine the behavioral and sensory processing effects of AT-121 administration in non-human primates. To examine the effects of AT-121 on nociception, they used the warm water tail withdrawal assay. Here animals’ tails are placed in 50 C water and the latency to withdraw their tail is measured. The authors determined that AT-121 produced dose-dependent antinociceptive effects against the acute noxious stimulus, 50 C water, as AT-121-treated animals showed full antinociception at the minimum effective dose (0.03 mg/kg). Importantly, this
Neuron
Spotlight dose also had a 3-hr duration that abated after 6 hr, suggesting a wide therapeutic window. Further examination revealed that combinatorial pretreatment with both NOP antagonist J-113397 and mu antagonist naltrexone provides a 30-fold rightward shift in AT-121’s dose-response curve, demonstrating that both NOP and mu contribute to antinociceptive effects of AT-121. Next, the authors employed a capsaicin-induced allodynia assay to examine AT-121 and pain sensitivity. Here the authors found that pretreatment with AT-121 exerted a dose-dependent inhibitory effect on capsaicin-induced thermal allodynia in 46 C water, demonstrating its capacity to significantly reduce pain hypersensitivity. Next, the authors determined whether AT-121 had any abuse liability because a critical feature of typical mu-opioid therapeutics is their propensity for abuse. To examine and compare the reinforcing effects of these compounds, the authors trained animals to selfadminister intravenous doses of cocaine, remifentanil, oxycodone, and varying doses of AT-121 on a progressive ratio schedule of reinforcement. While animals self-administer oxycodone compared to saline, there was no difference in AT121 and saline self-administration, suggesting that AT-121 does not cause reinforcement or reward-seeking behavior. In a separate experiment, the authors examined AT-121’s potential as a treatment for opioid abuse. Here they trained animals to self-administer oxycodone and administered naltrexone, buprenorphine, or AT-121 prior to progressive ratio testing. Similar to buprenorphine and naltrexone, pretreatment with AT-121 effectively attenuated the reinforcing effects of oxycodone as animals displayed lower responding for oxycodone. An essential finding in this new study is that AT-121 does not compromise physiological function. Here, the authors used radiotelemetric transmitters to monitor real-time respiratory and cardiovascular activity following AT-121 or heroin administration. In a single animal, the authors clearly demonstrate the risk of mu-mediated respiratory depression following heroin administration that ultimately required naltrexone to reverse and rescue the animal’s respiration. In
contrast, a high dose of AT-121 does not cause respiratory and cardiovascular concerns, nor do animals show sedation or motor impairments following treatment. These findings give further credence to AT-121’s promise as a suitable analgesic absent the risk of respiratory depression. Finally, the authors addressed another important complication of repeated treatment with standard opioid analgesics, that of physical dependence, opioidinduced hyperalgesia, and tolerance. Previous work has shown that primates and humans quickly develop physical dependence following repeated exposure to mu agonists (Ko et al., 2006). In such conditions, antagonist administration causes withdrawal symptoms that negatively impact respiratory and cardiovascular activity in primates (Ko et al., 2006). To examine if repeated AT-121 administration facilitates physical dependence, the authors repeatedly administered AT-121 or morphine for 3 days followed by antagonist administration on day 4. As expected, naltrexone precipitated withdrawal signs, while a combination of naltrexone and J-113397 did not produce any changes in AT-121-treated animals. The authors also examined whether AT-121’s repeated administration would potentiate hyperalgesia as compared to typical repeated morphine-potentiated hyperalgesia. Indeed, after short-term exposure to morphine, monkeys had a lower threshold to capsaicin-induced hypersensitivity, while AT-121-treated animals exhibited hypersensitivity similar to control animals. Furthermore, to evaluate chronic exposure to AT-121, animals were treated with daily injections of AT-121 or morphine for 4 weeks. Similar to previous studies, chronic morphine treatment drove a decrease in antinociceptive effects produced by morphine. However, chronic AT-121 treatment did not drive any tolerance to antinociceptive effects of AT-121. These results demonstrate that, contrary to typical mu agonists, repeated administration of AT-121 does not cause opioid-induced hyperalgesia and may slow the development of analgesic tolerance compared to morphine. The study by Ding et al. clearly demonstrates AT-121’s promise as a pain therapeutic, yet there are caveats in fully
understanding the consequences of chronic NOP/mu receptor administration. Many studies have evaluated NOP agonists’ short-term effects in modulating pain-related responding and reward-seeking behavior, yet the consequences of chronic NOP/mu receptor stimulation during chronic pain states or non-pain states has not been fully elucidated. Granted, the authors examined a relatively short ‘‘chronic’’ administration and found no effects on tolerance or hyperalgesia. However, implementing longer administration regimens as well as evaluating their effects in rewardseeking paradigms described here would greatly strengthen future studies. Furthermore, a critical assessment of how chronic AT-121 administration, and similar compounds, may influence general affective states is warranted as current studies are exploring the role of the NOP system in modulating negative affective states like anxiety and depression. In spite of these limitations, AT121 is a substantial addition to the rigorous development of novel, alternative pharmacotherapies needed for successful pain management and opioid abuse treatment. The authors provided an important contribution in elucidating the potential role bifunctional opioid agonists have in facilitating pain relief while paving the way for development of novel opioid analgesics with improved pharmacological profiles. DECLARATION OF INTERESTS M.R.B. is a co-founder of Neurolux, Inc., and serves as a scientific advisory board member of Condor Therapeutics. REFERENCES Austin Zamarripa, C., Edwards, S.R., Qureshi, H.N., Yi, J.N., Blough, B.E., and Freeman, K.B. (2018). The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats. Drug Alcohol Depend. 192, 158–162. Ding, H., Kiguchi, N., Yasuda, D., Daga, P.R., Polgar, W.E., Lu, J.J., Czoty, P.W., Kishioka, S., Zaveri, N.T., and Ko, M.C. (2018). A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci. Transl. Med. 10, eaar3483. Ko, M.C., Divin, M.F., Lee, H., Woods, J.H., and Traynor, J.R. (2006). Differential in vivo potencies of naltrexone and 6b-naltrexol in the monkey. J. Pharmacol. Exp. Ther. 316, 772–779.
Neuron 100, December 19, 2018 1281
Neuron
Spotlight Ko, M.C., Woods, J.H., Fantegrossi, W.E., Galuska, C.M., Wichmann, J., and Prinssen, E.P. (2009). Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology 34, 2088–2096. Lutfy, K., Hossain, S.M., Khaliq, I., and Maidment, N.T. (2001). Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br. J. Pharmacol. 134, 529–534.
1282 Neuron 100, December 19, 2018
National Academies of Sciences, Engineering, and Medicine (2017). Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (National Academies Press). Schro¨der, W., Lambert, D.G., Ko, M.C., and Koch, T. (2014). Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br. J. Pharmacol. 171, 3777–3800.
Volkow, N.D., and McLellan, A.T. (2016). Opioid abuse in chronic pain—misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263. Zaveri, N.T., Yasuda, D., Journigan, B.V., Daga, P.R., Jiang, F., and Olsen, C. (2013). Structure activity relationships of nociceptin receptor (NOP) ligands and the design of bifunctional NOP/mu opoid receptor-targeted ligands. Research and Development of Opioid Related Ligands 1131, 145–160.
Spotlight Pain Wars: A New Hope Kyle E. Parker1 and Michael R. Bruchas1,2,* 1Department
of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO, USA for the Neurobiology of Addiction, Pain, and Emotion, Departments of Anesthesiology and Pain Medicine, Department of Pharmacology, University of Washington, Seattle, WA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.11.045 2Center
Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics. Today, opioids binding to the mu-opioid receptor (mu) remain the primary analgesics used to treat pain conditions, driving an ever-increasing rate of opioid prescriptions over the last two decades. Unfortunately, long-term therapeutic regimens are complicated by side effects ranging from the milder constipation, vomiting, and nausea, to more severe side effects of respiratory depression, tolerance, physical dependence, and ultimately abuse liability and fatal overdose (Volkow and McLellan, 2016). These complications significantly impact the quality of life of patients and, according to several recent reports, are considered to be a driving force of the current opioid epidemic (National Academies of Sciences, Engineering, and Medicine, 2017). Clearly, the development of innovative therapies that separate opioid analgesia from these detrimental side effects is critical in curtailing this crisis. Understandably, recent scientific efforts are attempting to harness the potent analgesic effects of mu agonism with new strategies to minimize mu agonist-associated side effects. Most of these efforts have focused on the concept of ‘‘biased’’ opioid ligands, which can act via either G-protein or Arrestin-mediated pathways. However, while potentially promising in their own right, some of these ‘‘biased ligand’’ approaches at a single receptor have been revealed to have potential limitations (Austin Zamarripa et al., 2018). As a consequence of some of these limitations, investigators have also sought to re-examine non-selective opioid agonists and develop new bifunctional agonists as emerging basic science research has demonstrated the value of simultaneously targeting multiple opioid recep-
tors within peripheral and central pain and reward systems. Ultimately, these basic insights into the complex functional interactions of pain-modulating systems could also provide a path for devising new strategies in drug development. In recent years, substantial progress has been made in the development of mu and nociceptin opioid peptide (NOP) receptor bifunctional agonists. Mu and NOP share common signaling pathways to Gi-mediated inhibitory networks, and they are also both functionally expressed in pain and reward pathways. In some cases, NOP agonists have been shown to have broader potential for the treatment of neuropathic pain than classical opioids (Schro¨der et al., 2014). Specifically, NOP has been shown to be an encouraging target for the treatment of pain in non-human primates (Ko et al., 2009). Early studies have also indicated the potential of mixed mu/NOP agonists to alleviate side effects of typical mu agonists, including the development of tolerance and dependence. Interestingly, this effect could be due to the chronic desensitization of NOP signaling in reward and tolerance circuits (Lutfy et al., 2001). Additionally, observations from clinically prescribed opioid compounds like buprenorphine have driven a new rationale for the development of bivalent mu/NOP agonists as potential therapeutics in pain management (Zaveri et al., 2013). With their recent publication in Science Translational Medicine, Ding and colleagues sought to test this rationale with the development of a bifunctional mu/NOP agonist, AT-121, and then to thoroughly examine its potential as a non-addictive, analgesic alternative.
1280 Neuron 100, December 19, 2018 ª 2018 Elsevier Inc.
The authors began by developing bifunctional NOP/mu agonists through structure-guided drug design and optimization starting from a NOP-selective chemical scaffold. Following the chemical lead from their NOP ligand library, the authors used rational structure-activity relationship (SAR) optimization with Compound 1, the active-state NOP structure they had previously developed, to synthesize 5 additional analogs with improved NOP binding affinity. The authors then used in vitro pharmacological binding and functional assays to each of the opioid receptor subtypes to establish a rigorous pharmacological profile of each bifunctional agonist. From the data collected with these assays, Analog 5 (AT-121) showed high potency and partial agonist efficacy at both NOP and mu receptors. In comparison to all other analogs, the authors determined AT-121 as the best prototype ligand to explore their hypothesis that a balance between NOP and mu agonist efficacies could be a useful approach to develop new analgesics with reduced side effects. Following the synthesis of AT-121, the authors sought to determine the behavioral and sensory processing effects of AT-121 administration in non-human primates. To examine the effects of AT-121 on nociception, they used the warm water tail withdrawal assay. Here animals’ tails are placed in 50 C water and the latency to withdraw their tail is measured. The authors determined that AT-121 produced dose-dependent antinociceptive effects against the acute noxious stimulus, 50 C water, as AT-121-treated animals showed full antinociception at the minimum effective dose (0.03 mg/kg). Importantly, this
Neuron
Spotlight dose also had a 3-hr duration that abated after 6 hr, suggesting a wide therapeutic window. Further examination revealed that combinatorial pretreatment with both NOP antagonist J-113397 and mu antagonist naltrexone provides a 30-fold rightward shift in AT-121’s dose-response curve, demonstrating that both NOP and mu contribute to antinociceptive effects of AT-121. Next, the authors employed a capsaicin-induced allodynia assay to examine AT-121 and pain sensitivity. Here the authors found that pretreatment with AT-121 exerted a dose-dependent inhibitory effect on capsaicin-induced thermal allodynia in 46 C water, demonstrating its capacity to significantly reduce pain hypersensitivity. Next, the authors determined whether AT-121 had any abuse liability because a critical feature of typical mu-opioid therapeutics is their propensity for abuse. To examine and compare the reinforcing effects of these compounds, the authors trained animals to selfadminister intravenous doses of cocaine, remifentanil, oxycodone, and varying doses of AT-121 on a progressive ratio schedule of reinforcement. While animals self-administer oxycodone compared to saline, there was no difference in AT121 and saline self-administration, suggesting that AT-121 does not cause reinforcement or reward-seeking behavior. In a separate experiment, the authors examined AT-121’s potential as a treatment for opioid abuse. Here they trained animals to self-administer oxycodone and administered naltrexone, buprenorphine, or AT-121 prior to progressive ratio testing. Similar to buprenorphine and naltrexone, pretreatment with AT-121 effectively attenuated the reinforcing effects of oxycodone as animals displayed lower responding for oxycodone. An essential finding in this new study is that AT-121 does not compromise physiological function. Here, the authors used radiotelemetric transmitters to monitor real-time respiratory and cardiovascular activity following AT-121 or heroin administration. In a single animal, the authors clearly demonstrate the risk of mu-mediated respiratory depression following heroin administration that ultimately required naltrexone to reverse and rescue the animal’s respiration. In
contrast, a high dose of AT-121 does not cause respiratory and cardiovascular concerns, nor do animals show sedation or motor impairments following treatment. These findings give further credence to AT-121’s promise as a suitable analgesic absent the risk of respiratory depression. Finally, the authors addressed another important complication of repeated treatment with standard opioid analgesics, that of physical dependence, opioidinduced hyperalgesia, and tolerance. Previous work has shown that primates and humans quickly develop physical dependence following repeated exposure to mu agonists (Ko et al., 2006). In such conditions, antagonist administration causes withdrawal symptoms that negatively impact respiratory and cardiovascular activity in primates (Ko et al., 2006). To examine if repeated AT-121 administration facilitates physical dependence, the authors repeatedly administered AT-121 or morphine for 3 days followed by antagonist administration on day 4. As expected, naltrexone precipitated withdrawal signs, while a combination of naltrexone and J-113397 did not produce any changes in AT-121-treated animals. The authors also examined whether AT-121’s repeated administration would potentiate hyperalgesia as compared to typical repeated morphine-potentiated hyperalgesia. Indeed, after short-term exposure to morphine, monkeys had a lower threshold to capsaicin-induced hypersensitivity, while AT-121-treated animals exhibited hypersensitivity similar to control animals. Furthermore, to evaluate chronic exposure to AT-121, animals were treated with daily injections of AT-121 or morphine for 4 weeks. Similar to previous studies, chronic morphine treatment drove a decrease in antinociceptive effects produced by morphine. However, chronic AT-121 treatment did not drive any tolerance to antinociceptive effects of AT-121. These results demonstrate that, contrary to typical mu agonists, repeated administration of AT-121 does not cause opioid-induced hyperalgesia and may slow the development of analgesic tolerance compared to morphine. The study by Ding et al. clearly demonstrates AT-121’s promise as a pain therapeutic, yet there are caveats in fully
understanding the consequences of chronic NOP/mu receptor administration. Many studies have evaluated NOP agonists’ short-term effects in modulating pain-related responding and reward-seeking behavior, yet the consequences of chronic NOP/mu receptor stimulation during chronic pain states or non-pain states has not been fully elucidated. Granted, the authors examined a relatively short ‘‘chronic’’ administration and found no effects on tolerance or hyperalgesia. However, implementing longer administration regimens as well as evaluating their effects in rewardseeking paradigms described here would greatly strengthen future studies. Furthermore, a critical assessment of how chronic AT-121 administration, and similar compounds, may influence general affective states is warranted as current studies are exploring the role of the NOP system in modulating negative affective states like anxiety and depression. In spite of these limitations, AT121 is a substantial addition to the rigorous development of novel, alternative pharmacotherapies needed for successful pain management and opioid abuse treatment. The authors provided an important contribution in elucidating the potential role bifunctional opioid agonists have in facilitating pain relief while paving the way for development of novel opioid analgesics with improved pharmacological profiles. DECLARATION OF INTERESTS M.R.B. is a co-founder of Neurolux, Inc., and serves as a scientific advisory board member of Condor Therapeutics. REFERENCES Austin Zamarripa, C., Edwards, S.R., Qureshi, H.N., Yi, J.N., Blough, B.E., and Freeman, K.B. (2018). The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats. Drug Alcohol Depend. 192, 158–162. Ding, H., Kiguchi, N., Yasuda, D., Daga, P.R., Polgar, W.E., Lu, J.J., Czoty, P.W., Kishioka, S., Zaveri, N.T., and Ko, M.C. (2018). A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci. Transl. Med. 10, eaar3483. Ko, M.C., Divin, M.F., Lee, H., Woods, J.H., and Traynor, J.R. (2006). Differential in vivo potencies of naltrexone and 6b-naltrexol in the monkey. J. Pharmacol. Exp. Ther. 316, 772–779.
Neuron 100, December 19, 2018 1281
Neuron
Spotlight Ko, M.C., Woods, J.H., Fantegrossi, W.E., Galuska, C.M., Wichmann, J., and Prinssen, E.P. (2009). Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology 34, 2088–2096. Lutfy, K., Hossain, S.M., Khaliq, I., and Maidment, N.T. (2001). Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br. J. Pharmacol. 134, 529–534.
1282 Neuron 100, December 19, 2018
National Academies of Sciences, Engineering, and Medicine (2017). Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (National Academies Press). Schro¨der, W., Lambert, D.G., Ko, M.C., and Koch, T. (2014). Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br. J. Pharmacol. 171, 3777–3800.
Volkow, N.D., and McLellan, A.T. (2016). Opioid abuse in chronic pain—misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263. Zaveri, N.T., Yasuda, D., Journigan, B.V., Daga, P.R., Jiang, F., and Olsen, C. (2013). Structure activity relationships of nociceptin receptor (NOP) ligands and the design of bifunctional NOP/mu opoid receptor-targeted ligands. Research and Development of Opioid Related Ligands 1131, 145–160.