Accepted

Chronic pain interferes with daily functioning and is frequently accompanied by depression. Currently, traditional clinic treatments do not produce satisfactory analgesic effects and frequently result in various adverse effects. Pathogen recognition receptors (PRRs) serve as innate cellular sensors of danger signals, sense invading microorganisms, and initiate innate and adaptive immune responses. Among them, cGAS-STING alerts on the presence of both exogenous and endogenous DNA in the cytoplasm, and this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection, and cancer. An increasing numbers of evidence suggest that cGAS-STING pathway involves in the chronic pain process; however, its role remains controversial. In this narrative review, we summarize the recent findings on the involvement of the cGAS-STING pathway in chronic pain, as well as several possible mechanisms underlying its activation. As a new area of research, this review is unique in considering the cGAS-STING pathway in sensory neurons and glial cells as a part of a broader understanding of pain, including potential mechanisms of inflammation, immunity, apoptosis, and autophagy. It will provide new insight into the treatment of pain in the future.

Diabetes mellitus (DM) is one of the leading causes of morbidity and mortality worldwide. DM patients with diabetic neuropathy (DN) usually present with distal pain, sensorimotor polyneuropathy, postural hypotension, or erectile dysfunction. They also may present with other nerve pathologies such as inflammatory neuropathies and carpal tunnel syndrome. We conducted a systematic review and meta-analysis to assess the benefits of using sodium-glucose co-transporter-2 inhibitors (SGLT2Is) to manage DN. An extensive systematic literature review was conducted to include all articles published up to 24 February 2022. All clinical studies included patients with DM and reported the outcomes of SGLT2I on diabetes-associated neuropathy. Six studies were identified for meta-analysis, including a total of 5312 diabetic patients. The average age of the included patients ranged from 41 to 74 years and 34-73 years in the SGLT2I treatment and control groups, respectively. SGLT2I moderately improved the manifestations of diabetic peripheral neuropathy events and nerve conduction velocity. Furthermore, the SGLT2I treatment group had a statistically significant higher mean heart-to-mediastinum ratio (MD 0.41; 95% 0.17, 0.64; = 0.0006). However, the mean heart rates (MD -4.51; 95% -10.05, 1.04; = 0.11) and wash out rates (MD 2.13; 95% -8.48, 12.75; = 0.69) were not significantly different between the two groups. SGLT2Is could therefore be considered neuroprotective in patients with DN, possibly by considerably increasing the sensory and motor nerve conduction velocity, improving the clinical manifestations of DPN, and reducing sympathetic nervous system activity. http://www.crd.york.ac.uk/prospero/, identifier CRD42022312828.

Chronic pain is a long-standing unpleasant sensory and emotional feeling that has a tremendous impact on the physiological functions of the body, manifesting itself as a dysfunction of the nervous system, which can occur with peripheral and central sensitization. Many recent studies have shown that a variety of common immune cells in the immune system are involved in chronic pain by acting on the peripheral or central nervous system, especially in the autoimmune diseases. This article reviews the mechanisms of regulation of the sensory nervous system by neutrophils, macrophages, mast cells, B cells, T cells, and central glial cells. In addition, we discuss in more detail the influence of each immune cell on the initiation, maintenance, and resolution of chronic pain. Neutrophils, macrophages, and mast cells as intrinsic immune cells can induce the transition from acute to chronic pain and its maintenance; B cells and T cells as adaptive immune cells are mainly involved in the initiation of chronic pain, and T cells also contribute to the resolution of it; the role of glial cells in the nervous system can be extended to the beginning and end of chronic pain. This article aims to promote the understanding of the neuroimmune mechanisms of chronic pain, and to provide new therapeutic ideas and strategies for the control of chronic pain at the immune cellular level.

Physicians are challenged in treating pain patients due to the lack of quantifiable, objective methods of measuring pain in the clinic; pain sensation is multifaceted and subjective to each individual. There is a critical need for point-of-care quantification of accessible biomarkers to provide objective analyses beyond the subjective pain scales currently employed in clinical care settings. In the present study, we employed an animal model to test the hypothesis that circulating regulators of the inflammatory response directly associate with an objective behavioral response to inflammatory pain. Upon induction of localized paw inflammation, we measured the systemic protein expression of cytokines, and activity levels of matrix metalloproteinases (MMPs) that are known to participate in the inflammatory response at the site of injury and investigated their relationship to the behavioral response across a 24 h period. Intraplantar injection with 1% λ-carrageenan induced a significant increase in paw thickness across this timespan with maximal effects observed at the 8 h timepoint when locomotor activity was also impaired. Expression of the chemokines C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand 2 (CCL2) positively correlated with paw inflammation and negatively correlated with locomotor activity at 8 h. The ratio of MMP9 to MMP2 activity negatively correlated with paw inflammation at the 8 h timepoint. We postulate that the CXCL1 and CCL2 as well as the ratio of MMP9 to MMP2 activity may serve as predictive biomarkers for the timecourse of inflammation-associated locomotor impairment. These data define opportunities for the future development of a point-of-care device to objectively quantify biomarkers for inflammatory pain states.