The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

Accumulating evidence suggests the key role of the kynurenine pathway (KP) of the tryptophan metabolism in the pathogenesis of several diseases. Despite extensive research aimed at clarifying the mechanisms underlying the development and maintenance of neuropathic pain, the roles of KP metabolites in this process are still not fully known. Although the function of the peripheral KP has been known for several years, it has only recently been acknowledged that its metabolites within the central nervous system have remarkable consequences related to physiology and behavior. Both the products and metabolites of the KP are involved in the pathogenesis of pain conditions. Apart from the neuroactive properties of kynurenines, the KP regulates several neurotransmitter systems in direct or indirect ways. Some neuroactive metabolites are known to have neuroprotective properties (kynurenic acid, nicotinamide adenine dinucleotide cofactor), while others are toxic (3-hydroxykynurenine, quinolinic acid). Numerous animal models show that modulation of the KP may turn out to be a viable target for the treatment of diseases. Importantly, some compounds that affect KP enzymes are currently described to possess analgesic properties. Additionally, kynurenine metabolites may be useful for assessing response to therapy or as biomarkers in therapeutic monitoring. The following review describes the molecular site of action and changes in the levels of metabolites of the kynurenine pathway in the pathogenesis of various conditions, with a particular emphasis on their involvement in neuropathy. Moreover, the potential clinical implications of KP modulation in chronic pain therapy as well as the directions of new research initiatives are discussed.

Specialized Pro-Resolving Lipid Mediators: The Future of Chronic Pain Therapy?

Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.

The Interplay between Chronic Pain, Opioids, and the Immune System

Chronic pain represents one of the most serious worldwide medical problems, in terms of both social and economic costs, often causing severe and intractable physical and psychological suffering. The lack of biological markers for pain, which could assist in forming clearer diagnoses and prognoses, makes chronic pain therapy particularly arduous and sometimes harmful. Opioids are used worldwide to treat chronic pain conditions, but there is still an ambiguous and inadequate understanding about their therapeutic use, mostly because of their dual effect in acutely reducing pain and inducing, at the same time, tolerance, dependence, and a risk for opioid use disorder. In addition, clinical studies suggest that opioid treatment can be associated with a high risk of immune suppression and the development of inflammatory events, worsening the chronic pain status itself. While opioid peptides and receptors are expressed in both central and peripheral nervous cells, immune cells, and tissues, the role of opioids and their receptors, when and why they are activated endogenously and what their exact role is in chronic pain pathways is still poorly understood. Thus, in this review we aim to highlight the interplay between pain and immune system, focusing on opioids and their receptors.

New hope on the horizon of chronic pain therapy; targeting PI3K, proinflammatory cytokines/AKT/nitric oxide

Pain is one of the most debilitating and unpleasant sensory or emotional condition which present itself in the form of complex phenomena. Safe and effective drug treatment for chronic pain is still a gigantic challenge in the field of research and quality of life. Recently phosphotidylinositide-3-kinase (PI3K) and its downstream regulator emerged as appealing targets for the development of new drugs having immense potential in various major disorders[1]. Researcher’s targeted different PI3K downstream signaling components both in central and peripheral level of nervous system using various models of chronic pain. Emphasis must be put on the importance of PI3K and its downstream molecules such as Akt, proinflammatory cytokines and nitric oxide as a potential target for the treatment of chronic pain. Researchers are paying serious efforts to identify those molecules which have high clinical outcome with least chances of side effects.

Pharmacogenomics in chronic pain therapy: from disease to treatment and challenges for clinical practice

Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug–gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug–gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.

OxyContin and the McDonaldization of chronic pain therapy in the USA

Principles and practices gleaned from successful business enterprises have been used to transform the practice of medicine for decades. McDonaldization is the process in which principles which govern fast-food businesses, are applied to the practice of medicine. When left unchecked, the application of these principles can have devastating consequences, as in the treatment of chronic, non-malignant pain with OxyContin. At a time when there was growing concern about the under treatment of pain, Purdue Pharma introduced OxyContin, providing an efficient, predictable way of treating chronic pain. The liberal prescription of this drug contributed, and continues to contribute, to the opioid epidemic we see today. So, in confronting this epidemic, we must first understand the process of McDonaldization that has brought us here and then provide safe and effective chronic pain therapies even if they are expensive, time-consuming to deliver, difficult to measure, and unpredictable in their outcomes—all things we’ve grown to detest in our McDonaldized healthcare system.