SBIR-STTR Award

Sickle cell disease (SCD) is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance and dependence, remain a sub-optimal approach to treat SCD pain, particularly when used on a continued basis. Sickle patients therefore live with recurrent difficult-to-treat pain, resulting in frequent hospitalization and loss of productivty. Thus there is a critical need to develop effective therapies devoid of addiction and tolerance to treat severe pain in SCD. We have recently demonstrated that nociceptin receptor (NOP) agonists have significant anti-nociceptive and anti-allodynic effects in an animal model of chronic pain, with efficacies comparable to that of the opioid morphine, in the same model. We further demonstrated that bifunctional NOP/opioid agonists also possess anti-allodynic activity, and do not develop tolerance and have no rewarding effects on their own. The nociceptin receptor NOP and its endogenous ligand nociceptin/orphanin FQ (N/OFQ) are widely distributed in the brain and spinal cord in regions involved in nociceptive responses and are a target for pain therapeutics. The NOP system also modulates opioid effects such as anti-nociception, opioid-induced tolerance and reward. Therefore, from a therapeutic standpoint, NOP receptor agonism appears to be a broad, promising pharmacological strategy to provide pain relief in sickle cell pain, without the liabilities associated with opioid- based therapies, such as constipation, tolerance and dependence. This application therefore proposes proof- of-concept studies to investigate the efficacy of NOP agonists in the treatment of chronic pain associated with sickle cell disease, with the following Specific Aims: Aim 1: To identify one NOP agonist and one bifunctional NOP agonist/mu partial agonist, which have suitable drug-like characteristics and brain penetration, for evaluation in efficacy studies. Aim 2: To determine the analgesic ability of NOP agonist and NOP agonist/mu partial agonist on pain in sickle mice. We will examine the effect on, (a) tonic hyperalgesia representing chronic pain, (b) acute pain due to vaso-occlusive "crises" incited by hypoxia/reoxygenation, and (c) inflammation and organ pathology to rule out the adverse effects of NOP-based analgesics. We will use relevant mouse models of sickle cell disease recently developed in our laboratory and employ several different measures of pain including testing for cutaneous and deep tissue hyperalgesia and sensitivity to heat and cold, which will provide comprehensive investigation on different pain characteristics observed clinically in patients with SCD. These studies will facilitate the translation of the promising efficacy of NOP receptor agonists in chronic pain into therapeutic use to expand the options for pain relief in SCD, without inadvertent opioid-related side effects. Promising, efficacious NOP agonists identified from this project can be further developed as potential pharmacotherapy for the treatment of pain in SCD.

Public Health Relevance:
Patients with sickle cell disease (SCD) suffer with severe pain throughout life, which is challenging to treat. Opioids are the only therapy widely used but unfortunately are associated with side effects (constipation) and development of tolerance and addiction. Nociceptin receptor (NOP) agonists are able to produce opioid-level analgesia without the opioid-related side effects, such as tolerance and dependence, in models of pain. If they demonstrate proof-of-efficacy in the animal models of SCD, as proposed in this project, they would offer a tremendous therapeutic advantage to treat pain in SCD without opioid-related side effects.

Public Health Relevance Statement:
Patients with sickle cell disease (SCD) suffer with severe pain throughout life, which is challenging to treat. Opioids are the only therapy widely used but unfortunately are associated with side effects (constipation) and development of tolerance and addiction. Nociceptin receptor (NOP) agonists are able to produce opioid-level analgesia without the opioid-related side effects, such as tolerance and dependence, in models of pain. If they demonstrate proof-of-efficacy in the animal models of SCD, as proposed in this project, they would offer a tremendous therapeutic advantage to treat pain in SCD without opioid-related side effects.

NIH Spending Category:
Hematology; Neurosciences; Pain Conditions - Chronic; Pain Research; Rare Diseases; Sickle Cell Disease

Project Terms:
Absence of pain sensation; Acute; Acute Pain; addiction; Adverse effects; African American; Age; Agonist; Analgesics; Animal Model; base; Biological Assay; Brain; Characteristics; Child; Chronic; chronic pain; Constipation; Cutaneous; Data; Dependence; Development; Dose; effective therapy; Evaluation; Exhibits; Family; grasp; Heating; Hemolytic Anemia; Hispanics; Hospitalization; Human; Hyperalgesia; Hypoxia; improved; In Vitro; in vivo; Inflammation; insight; Investigation; Labor Pain; Laboratories; Life; Ligands; Measures; member; Modeling; Morphine; mouse model; Mus; nociceptin; nociceptin receptor; Nociception; nociceptive response; novel; novel strategies; Opioid; Opioid Receptor; Organ; Pain; Pain management; Pathology; Patients; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Process; Quality of life; receptor; Recurrence; Reperfusion Injury; Research Personnel; Rewards; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; small molecule; Spinal Cord; standard of care; System; Testing; Therapeutic; Therapeutic Uses; Tissues; Transgenic Mice; Translations; United States; vaso-occlusive pain

Every year, about 100 million adult Americans experience some form of pain, a condition that costs the nation between $560 billion and $635 billion annually in lost productivity and treatment. The recently released `National Pain Strategy' developed by the NINDS's IPRCC, recognizes acute and chronic pain as a serious and costly public health issue, and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US. Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief. However, opioid analgesics (which are mainly mu opioid receptor (MOP) agonists) are controlled substances that have abuse potential and are riddled with other side effects such as constipation, nausea, and tolerance, which impede their long-term safety and effectiveness. There is clearly a need for new analgesics that provide opioid-like efficacies without the liabilities of opioid pain-killers. he nociceptin opioid receptor (NOP), the 4th member of the opioid receptor family, and its endogenous peptide ligand, nociceptin/orphanin FQ (N/OFQ) are emerging new targets for pain medications. The NOP receptor and N/OFQ are found throughout in pain-processing pathways in the brain and spinal cord, and modulate opioid function by blocking opioid reward and even tolerance. We and others have shown that the natural peptide N/OFQ and small-molecule NOP agonists and bifunctional' NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain, are non-rewarding and do not develop tolerance. These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid-related liabilities. In our Phase I project, we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell disease'(SCD), which develops spontaneous hyperalgesia similar to the condition in sickle patients. SCD is associated with severe pain, which remains a major challenge to treat. Opioids are the current standard of care, but due to side effects and development of tolerance, remain a sub-optimal approach to treat SCD pain, particularly when needed on a continued basis. Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD. Our Phase I studies showed that the NOP agonist-mu low efficacy agonist AT-200 showed significant antinociceptive efficacy in sickle mice, more potent and longer-lasting than high-dose morphine. AT-200 also showed a sustained analgesic effect, without tolerance development. These promising data that NOP agonists and/or NOP-mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain. In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP-targeted `preclinical lead candidates', which are optimized for their drug-like suitability and novelty, hav in vivo efficacy in pain models in rodents and nonhuman primates, and preliminary evaluation of toxicity, that are ready to be advanced into IND-enabling studies for development as pain medications.

Public Health Relevance Statement:


Public Health Relevance:
This application proposes early translational studies of lead optimization and efficacy confirmation to develop `preclinical lead candidates' as a novel class of analgesics that have potent opioid-like analgesia but without opioid liabilities of constipation tolerance and abuse liability. Successful completion of these studies will validate a new approach for the treatment of chronic and severe acute pain and importantly, result in preclinical drug candidates that are ready to be advanced into IND-enabling studies for development as novel pain medications.

NIH Spending Category:
Drug Abuse (NIDA only); Hematology; Neurodegenerative; Neurosciences; Orphan Drug; Pain Conditions - Chronic; Pain Research; Peripheral Neuropathy; Rare Diseases; Sickle Cell Disease; Substance Abuse

Project Terms:
Absence of pain sensation; Acute Pain; Adult; Adverse effects; Affect; African American; Agonist; allodynia; American; Analgesics; Animal Model; base; Biological Assay; Biological Availability; Brain; Capsaicin; Child; Chronic; chronic pain; Clinical; Clinical Trials; Constipation; cost; cytokine; Data; design; Development; Disease; Dose; drug candidate; drug development; Drug Kinetics; Drug Prescriptions; effective therapy; Effectiveness; Evaluation; experience; Family; Future; Hispanics; Human; Hyperalgesia; Hypoxia; improved; In Vitro; in vivo; Inflammatory; inflammatory pain; Ion Channel; Lead; Life; Ligands; Manuscripts; mast cell; member; Metabolic; Modality; Modeling; Modification; Monkeys; Morphine; mouse model; mu opioid receptors; Mus; Naloxone; Narcotic Antagonists; Nausea; nociceptin; nociceptin receptor; Nociception; nonhuman primate; novel; novel strategies; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Pain; Pain management; Pain Research; painful neuropathy; patch clamp; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; phase 1 study; Plasma; pre-clinical; preference; Process; Productivity; Public Health; public health relevance; Quality of life; receptor; receptor binding; Receptors, Opioid, delta; Research; Rewards; Rodent; Rodent Model; Safety; Sickle Cell Anemia; sickling; small molecule; Solid; Spinal Cord; standard of care; Symptoms; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; translational study; United States; Work