Pharmacology/Drug Development

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world's population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an "epidemic" of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.

Nerve growth factor (NGF) plays a crucial role in pain modulation and is being considered as a new therapeutic target for pain therapy. The purpose of this meta-analysis was to study the efficacy of anti-NGF antibodies for the treatment of osteoarthritis pain and chronic low-back pain, and to provide evidence and direction for further research and practice.

Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.

Substance use disorders represent a global public health issue. This mental health disorder is hypothesized to result from neurobiological changes as a result of chronic drug exposure and clinically manifests as inappropriate behavioral allocation toward the procurement and use of the abused substance and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g., social relationships, work). The dynorphin/kappa-opioid receptor (KOR) is one receptor system that has been altered following chronic exposure to drugs of abuse (e.g., cocaine, opioids, alcohol) in both laboratory animals and humans, implicating the dynorphin/KOR system in the expression, mechanisms, and treatment of substance use disorders. KOR antagonists have reduced drug self-administration in laboratory animals under certain experimental conditions, but not others. Recently, several human laboratory and clinical trials have evaluated the effectiveness of KOR antagonists as candidate pharmacotherapies for cocaine or tobacco use disorder to test hypotheses generated from preclinical studies. KOR antagonists failed to significantly alter drug use metrics in humans suggesting translational discordance between some preclinical drug self-administration studies and consistent with other preclinical drug self-administration studies that provide concurrent access to an alternative nondrug reinforcer (e.g., food). The implications of this translational discordance and future directions for examining the therapeutic potential of KOR agonists or antagonists as candidate substance use disorder pharmacotherapies are discussed.