Chronic pain AND neurobiology

Social dominance is a universal phenomenon among grouped animals that profoundly affects survival, health, and reproductive success by determining access to resources, and exerting a powerful influence on subsequent behavior. However, the understanding of pain and anxiety comorbidities in dominant or subordinate animals suffering from chronic pain is not well-defined. Here, we provide evidence that subordinate mice are more susceptible to pain-induced anxiety compared to dominant mice. We propose that the gut microbiota may play a mediating role in this mechanism...

The brain and spinal cord (SC) are both targeted by various hormones, including steroid hormones. However, investigations of the modulatory role of hormones on neurobiological functions usually focus only on the brain. The SC received little attention although this structure pivotally controls motor and sensory functions. Here, we critically reviewed key data showing that the process of neurosteroid biosynthesis or neurosteroidogenesis occurring in the SC plays a pivotal role in the modulation of peripheral nerve injury-induced chronic pain (PNICP) or neuropathic pain...

The aim of this study was to investigate the potential therapeutic applications of (+)-catechin in the treatment of neuropathic pain. In vivo study, 32 SD rats were randomly divided into four groups: sham group, chronic constriction injury (CCI) group, CCI + ibuprofen group and CCI+ (+)-catechin group. They were subjected to behavioural tests, ELISA, immunohistochemistry and Western blotting. The mechanisms involved were investigated using specific inhibitors in cell experiments. Results of in vivo experiments showed that (+)-catechin could reduce the cold sensitivity pain in a rat model of CCI; ELISA and immunohistochemistry results showed that (+)-catechin could decrease the levels of IL-8, IL-6, TNF-α, CCL2 and CCL5 in serum and the expression levels of nNOS, COX2, IL6, TNF-α, IBA-1 and CSF1R in DRG of CCI rats...

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR)...

Chronic craniofacial pain is intractable and its mechanisms remain unclarified. The rostral ventromedial medulla (RVM) plays a crucial role in descending pain facilitation and inhibition. It is unclear how the descending circuits from the RVM to spinal trigeminal nucleus (Sp5) are organized to bidirectionally modulate craniofacial nociception. We used viral tracing, in vivo optogenetics, calcium signaling recording, and chemogenetic manipulations to investigate the structure and function of RVM-Sp5 circuits...

While neural oscillations play a critical role in sensory perception, it remains unclear how these rhythms function under conditions of neuropathic allodynia. Recent studies demonstrated that the anterior cingulate cortex (ACC) is associated with the affective-aversive component of pain, and plasticity changes in this region are closely linked to abnormal allodynic sensations. Here, to study the mechanisms of allodynia, we recorded local field potentials (LFPs) in the bilateral ACC of awake-behaving rats and compared the spectral power and center frequency of brain oscillations between healthy and CCI (chronic constriction injury) induced neuropathic pain conditions...

BACKGROUND: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain...

OBJECTIVE: Alterations in autonomic function are evident in some chronic pain conditions but have not been thoroughly examined in people with osteoarthritis (OA). The study aimed to examine resting autonomic nervous system (ANS) function in people with knee OA, and the response of the autonomic and nociceptive systems to acute stress. METHODS: A preliminary cross-sectional study was undertaken involving people with knee OA ( n  = 14), fibromyalgia ( n  = 13), and pain-free controls ( n  = 15)...

Circular RNAs are a novel class of RNA molecules that are covalently closed into a ring structure. They are an epigenetic regulatory mechanism, and their best-studied function is regulation of microRNA activity. As such circular RNAs may be involved in the switch from acute to chronic pain. They have previously been studied in the context of neuropathic pain models, but their importance in inflammation-induced chronic pain models is unexplored. Microarray analysis of dorsal root ganglia collected in the late phase of collagen antibody-induced arthritis (day 59) were used to elucidate the relevance of circular RNAs in the mechanical hypersensitivity caused by this model...

Chronic pain develops following injury in approximately 20% of adolescents, at twice the rate in females than males. Adverse childhood experiences also increase the risk for poor health outcomes, such as chronic pain. Emerging literature suggests the cerebellum to be involved in pain processing, however detailed explorations into how the cerebellum contributes to pain are lacking. Therefore, this study aimed to characterise chronic pain outcomes and cerebellar gene expression changes following early life stress and injury in both sexes...

Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP ) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice...

The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain...

N -acyl-ethanolamine (NAEs) serve as key endogenous lipid mediators as revealed by manipulation of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for metabolizing NAEs. Preclinical studies focused on FAAH or NAE receptors indicate an important role for NAE signaling in nociception and affective behaviors. However, there is limited information on the role of NAE biosynthesis in these same behavioral paradigms. Biosynthesis of NAEs has been attributed largely to the enzyme N -acylphosphatidylethanolamine Phospholipase D (NAPE-PLD), one of three pathways capable of producing these bioactive lipids in the brain...

We are exposed to various external and internal threats which might hurt us. The role of taking flexible and appropriate actions against threats is played by "the limbic system" and at the heart of it there is the ventral tegmental area and nucleus accumbens (brain reward system). Pain-related fear causes excessive excitation of amygdala, which in turn causes the suppression of medial prefrontal cortex, leading to chronification of pain. Since the limbic system of chronic pain patients is functionally impaired, they are maladaptive to their situations, unable to take goal-directed behavior and are easily caught by fear-avoidance thinking...

Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice...

INTRODUCTION: Behavioral therapies, including cognitive behavioral therapy, hypnotherapy and stress management activities, have emerged as effective treatments for irritable bowel syndrome (IBS), a female predominant disorder of the brain-gut axis. IBS, affecting over 10% of the global population, typically presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While the mechanisms underlying how behavioral therapies treat IBS are still elusive, we had previously shown that chronic stress alters gene expression in brain regions critical for stress processing and nociception...

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain and psychological distress. Research suggests people with FM experience increased somatosensory sensitization which generalizes to other sensory modalities and may indicate neural hyperexcitability. However, the available evidence is limited, and studies including measures of neural responsivity across sensory domains and both central and peripheral aspects of the neuraxis are lacking. Thirty-nine participants (51.5 ± 13...

Central sensitization is an important pathophysiological mechanism underlying chronic migraine (CM). Previous studies have shown that microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to central sensitization. Toll-like receptor 2 (TLR2) is a receptor expressed on the membrane of microglia and participates in central sensitization in inflammatory and chronic pain; however, its role in CM is unclear. Therefore, this study investigated TLR2 involvement in CM in detail...

Chronic pain is one of the most devastating and unpleasant conditions, associated with many pathological states. Tissue or nerve injuries induce extensive neurobiological plasticity in nociceptive neurons, which leads to chronic pain. Recent studies suggest that cyclin-dependent kinase 5 (CDK5) in primary afferents is a key neuronal kinase that modulates nociception through phosphorylation under pathological conditions. However, the impact of the CDK5 on nociceptor activity especially in human sensory neurons is not known...

As one of the commonly used therapies for pain-related diseases in clinical practice, electroacupuncture (EA) has been proven to be effective. In chronic pain, neurons in the anterior cingulate cortex (ACC) have been reported to be hyperactive, while the mechanism by which cannabinoid type 1 receptors (CB1Rs) in the ACC are involved in EA-mediated analgesic mechanisms remains to be elucidated. In this study, we investigated the potential central mechanism of EA analgesia. A combination of techniques was used to detect the expression and function of CB1R, including quantitative real-time PCR (q-PCR), western blot (WB), immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and in vivo multichannel optical fibre recording, and neuronal activity was examined by in vivo two-photon imaging and in vivo electrophysiological recording...