Accepted

The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances in molecular biological techniques and the development of a specific pharmacological inhibitor for cytohesins, SecinH3, have revealed the functional involvement of the cytohesin-Arf pathway in diverse neuronal functions from the formation of axons and dendrites, axonal pathfinding, and synaptic vesicle recycling, to pathophysiological processes including chronic pain and neurotoxicity induced by proteins related to neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we review the physiological and pathological roles of the cytohesin-Arf pathway in neurons and discuss the future directions of this research field.

Neuropathic pain is often chronic and can persist after overt tissue damage heals, suggesting that its underlying mechanism involves the alteration of neuronal function. Such an alteration can be a direct consequence of nerve damage or a result of neuroplasticity secondary to the damage to tissues or to neurons. Recent studies have shown that neuroplasticity is linked to causing neuropathic pain in response to nerve damage, which may occur adjacent to or remotely from the site of injury. Furthermore, studies have revealed that neuroplasticity relevant to chronic pain is modulated by microglia, resident immune cells of the central nervous system (CNS). Microglia may directly contribute to synaptic remodeling and altering pain circuits, or indirectly contribute to neuroplasticity through property changes, including the secretion of growth factors. We herein highlight the mechanisms underlying neuroplasticity that occur in the somatosensory circuit of the spinal dorsal horn, thalamus, and cortex associated with chronic pain following injury to the peripheral nervous system (PNS) or CNS. We also discuss the dynamic functions of microglia in shaping neuroplasticity related to chronic pain. We suggest further understanding of post-injury ectopic plasticity in the somatosensory circuits may shed light on the differential mechanisms underlying nociceptive, neuropathic, and nociplastic-type pain. While one of the prominent roles played by microglia appears to be the modulation of post-injury neuroplasticity. Therefore, future molecular- or genetics-based studies that address microglia-mediated post-injury neuroplasticity may contribute to the development of novel therapies for chronic pain.

Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the interface of persistent pain, sleep, and obesity in 71 men and 122 women undergoing tertiary pain care. They were examined for patterns in d = 97 metabolomic markers that segregated patients with a relatively benign pain phenotype (low and little bothersome pain) from those with more severe clinical symptoms (high pain intensity, more bothersome pain, and co-occurring problems such as sleep disturbance). Two independent lines of data analysis were pursued. First, a data-driven supervised machine learning-based approach was used to identify the most informative metabolic markers for complex phenotype assignment. This pointed primarily at adenosine monophosphate (AMP), asparagine, deoxycytidine, glucuronic acid, and propionylcarnitine, and secondarily at cysteine and nicotinamide adenine dinucleotide (NAD) as informative for assigning patients to clinical pain phenotypes. After this, a hypothesis-driven analysis of metabolic pathways was performed, including sleep and obesity. In both the first and second line of analysis, three metabolic markers (NAD, AMP, and cysteine) were found to be relevant, including metabolic pathway analysis in obesity, associated with changes in amino acid metabolism, and sleep problems, associated with downregulated methionine metabolism. Taken together, present findings provide evidence that metabolomic changes associated with co-occurring problems may play a role in the development of severe pain. Co-occurring problems may influence each other at the metabolomic level. Because the methionine and glutathione metabolic pathways are physiologically linked, sleep problems appear to be associated with the first metabolic pathway, whereas obesity may be associated with the second.

The United States opioid epidemic is fueled by illicit opioid abuse and prescription opioid misuse and abuse. Consequently, cases of opioid use disorder (OUD, opioid addiction), opioid overdose, and related deaths have increased since the year 2000. Naloxone is an opioid antagonist that rapidly reverses opioid intoxication to prevent death from overdose. It is one of the major risk mitigation strategies recommended in the 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain. However, despite the exponential increase in dispensing and distribution of naloxone, opioid overdose and related deaths have continued to increase; suggesting that the increased naloxone supply still lags the need. This discordance is attributed at least in part to the negative attitude toward naloxone, which is based on the belief that naloxone is only meant for "addicts" and "abusers" (OUD patients). This negative attitude or so-called naloxone stigma is therefore considered a major barrier for naloxone distribution and consequently, overdose-death prevention efforts. This article presents evidence that challenges common assertions about OUD stigma being the sole and direct driving force behind naloxone stigma, and the purported magnitude of the barrier that naloxone stigma constitutes for naloxone distribution programs among the stakeholders (patients, pharmacists, and prescribers). The case was then made to operationalize and quantify the construct among the stakeholders to determine the extent to which OUD stigma drives naloxone stigma, and the relative impact of naloxone stigma as a barrier for naloxone distribution efforts.

Chronic pain is a severely debilitating condition that reflects a long-term sensitization of signal transduction in the afferent pain pathway. Among the key players in this pathway are T-type calcium channels, in particular the Ca3.2 isoform. Because of their biophysical characteristics, these channels are ideally suited towards regulating neuronal excitability. Recent evidence suggests that T-type channels contribute to excitability of neurons all along the ascending and descending pain pathways, within primary afferent neurons, spinal dorsal horn neurons, and within pain-processing neurons in the midbrain and cortex. Here we review the contribution of T-type channels to neuronal excitability and function in each of these neuronal populations and how they are dysregulated in chronic pain conditions. Finally, we discuss their molecular pharmacology and the potential role of these channels as therapeutic targets for chronic pain.