pain neurobiology

Periaqueductal gray (PAG), an integration center for neuronal signals, is located in the midbrain and regulates multiple physiological and pathological behaviors, including pain, defensive and aggressive behaviors, anxiety and depression, cardiovascular response, respiration, and sleep-wake behaviors. Due to the different neuroanatomical connections and functional characteristics of the four functional columns of PAG, different subregions of PAG synergistically regulate various instinctual behaviors. In the current review, we summarized the role and possible neurobiological mechanism of different subregions of PAG in the regulation of pain, defensive and aggressive behaviors, anxiety, and depression from the perspective of the up-down neuronal circuits of PAG...

This study explores the molecular underpinnings of neuropathic pain (NPP) and neuroinflammation, focusing on the role of TRIM28 in the regulation of autophagy and microglia ferroptosis. Leveraging transcriptomic data associated with NPP, we identified TRIM28 as a critical regulator of ferroptosis. Through comprehensive analysis, including Gene Ontology enrichment and protein-protein interaction network assessments, we unveiled GSK3B as a downstream target of TRIM28. Experimental validation confirmed the capacity of TRIM28 to suppress GSK3B expression and attenuate autophagic processes in microglia...

There is considerable comorbidity across externalizing and internalizing behavior dimensions of psychopathology. We applied genomic structural equation modeling (gSEM) to genome-wide association study (GWAS) summary statistics to evaluate the factor structure of externalizing and internalizing psychopathology across 16 traits and disorders among European-ancestry individuals (n's = 16,400 to 1,074,629). We conducted GWAS on factors derived from well-fitting models. Downstream analyses served to identify biological mechanisms, explore drug repurposing targets, estimate genetic overlap between the externalizing and internalizing spectra, and evaluate causal effects of psychopathology liability on physical health...

Fibromyalgia (FM) is a painful chronic condition that significantly impacts the quality of life, posing challenges for clinical management. Given the difficulty of understanding the pathophysiology and finding new therapeutics, this study explored the effects of a medicinal plant, E. brasiliensis, in an FM model induced by reserpine in Swiss mice. Animals were treated with saline 0.9% (vehicle), duloxetine 10 mg/kg (positive control), or hydroalcoholic extract of E. brasiliensis leaves 300 mg/kg (HEEb). Nociceptive parameters, as well as locomotion, motor coordination, strength, anxiety, and depressive-like behaviors, were evaluated for 10 days...

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia...

BACKGROUND: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. METHODS: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury...

Thermosensation, the ability to detect and estimate temperature, is an evolutionarily conserved process that is essential for survival. Thermosensing is impaired in various pain syndromes, resulting in thermal allodynia, the perception of an innocuous temperature as painful, or thermal hyperalgesia, an exacerbated perception of a painful thermal stimulus. Several behavioral assays exist to study thermosensation and thermal pain in rodents, however, most rely on reflexive withdrawal responses or the subjective quantification of spontaneous nocifensive behaviors...

The appearance of contralateral effects after unilateral injury has been shown in various experimental pain models, as well as in clinics. They consist of a diversity of phenomena in contralateral peripheral nerves, sensory ganglia, or spinal cord: from structural changes and altered gene or protein expression to functional consequences such as the development of mirror-image pain (MP). Although MP is a well-documented phenomenon, the exact molecular mechanism underlying the induction and maintenance of mirror-like spread of pain is still an unresolved challenge...

Accumulating evidence strongly supports that PINK1 mutation can mediate mitochondrial autophagy dysfunction in dopaminergic neurons. This study was conducted to determine the role of PINK1 in the pathogenesis of postherpetic neuralgia (PHN) and find new targets for its treatment. A rigorous literature review was conducted to identify 2801 compounds from more than 200 plants in Asia. Virtual screening was used to shortlist the compounds into 20 groups based on their binding energies. MM/PBSA was used to further screen the compound dataset, and vitexin, luteoloside, and 2'-deoxyadenosine-5'-monophosphate were found to have a score of - 59...

BACKGROUND AND AIMS: Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options...

The role of circular RNAs (circRNAs) in neuropathic pain is linked to the fundamental physiological mechanisms involved. However, the exact function of circRNAs in the context of neuropathic pain is still not fully understood. The functional impact of circGRIN2B on the excitability of dorsal root ganglion (DRG) neurons was investigated using siRNA or overexpression technology in conjunction with fluorescence in situ hybridization and whole-cell patch-clamp technology. The therapeutic efficacy of circGRIN2B in treating neuropathic pain was confirmed by assessing the pain threshold in a chronic constrictive injury (CCI) model...

Chronic pain is a significant problem in adults; however, it can also be challenging to evaluate and manage effectively in pediatric and adolescent populations. Many theories implicate different factors that cause pain to become chronic, more severe, or more detrimental to function. There is emerging evidence for the role of generalized multisensory sensitivity (MSS) as a contributing factor to chronic pain in the adult population; however, similar evidence in the pediatric literature is lacking. Thus, the purpose of this case series is to highlight the clinical use of MSS assessment in children and adolescents with chronic pain to better phenotype and provide targeted treatment...

This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), a major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury of the sciatic nerve, the research assessed pain behaviors and the impact of rTMS on molecular interactions within the amygdala. Through a comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Withdrawal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, and Co-Immunoprecipitation (Co-IP), the study focused on the expression and interaction of integrin αvβ3 and its receptor P2X7R...

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse...

Monoamine-targeting antidepressants serve as frontline medications for chronic pain and associated comorbidities. While persistent anti-allodynic properties of antidepressants generally require weeks of treatment, several groups have demonstrated acute analgesic effects within hours of administration, suggesting a role in non-mesocorticolimbic pain processing regions such as the peripheral nervous system. To further explore this possibility, after four weeks of spared nerve injury or sham surgeries, we systemically administered desipramine or saline for an additional three weeks and performed whole transcriptome RNA sequencing on L3-6 dorsal root ganglia...

Painful traumatic trigeminal neuropathy (PTTN) is a chronic neuropathic pain that may develop following injury to the trigeminal nerve. Etiologies include cranio-orofacial trauma that may result from dental, surgical, or anesthetic procedures or physical trauma, such as a motor vehicle accident. Following nerve injury, there are various mechanisms, including peripheral and central, as well as phenotypic changes and genetic predispositions that may contribute to the development of neuropathic pain. In this article, we review current literature pertaining to the cellular processes that occur following traumatic damage to the trigeminal nerve, also called cranial nerve V, that results in chronic neuropathic pain...

INTRODUCTION: Positive and negative treatment expectations are powerful modulators of health and treatment outcomes. A substantial part of treatment success is due to contextual factors modulating patient's expectations towards a treatment. Consequently, treatment expectations should be a target of therapeutic interventions themselves. OBJECTIVES: This article highlights the neurobiological underpinnings of treatment expectations as well as strategies to modulate contextual factors to optimize treatment outcomes in daily clinical settings...

Potassium voltage-gated channel subfamily a member 2 (Kv1.2, encoded by KCNA2) is highly expressed in the central and peripheral nervous systems. Based on the patch clamp studies, gain-of function (GOF), loss-of-function (LOF), and a mixed type (GOF/LOF) variants can cause different conditions/disorders. KCNA2-related neurological diseases include epilepsy, intellectual disability (ID), attention deficit/hyperactive disorder (ADHD), autism spectrum disorder (ASD), pain as well as autoimmune and movement disorders...

INTRODUCTION: Primary headaches, including migraines and cluster headaches, are highly prevalent disorders that significantly impact quality of life. Several factors suggest a key role for the hypothalamus, including neuroimaging studies, attack periodicity, and the presence of altered homeostatic regulation. The orexins are two neuropeptides synthesized almost exclusively in the lateral hypothalamus with widespread projections across the central nervous system. They are involved in an array of functions including homeostatic regulation and nociception, suggesting a potential role in primary headaches...

Neuropathic pain (NPP) is a common type of chronic pain. Glial cells, including astrocytes (AS), are believed to play an important role in the progression of NPP. AS cells can be divided into various types based on their expression profiles, among which A1 and A2 types have clear functions. A1-type AS cells are neurotoxic, while A2-type AS cells exert neuroprotective functions. Some types of lysophosphatidic acid receptors (LPAR) have been shown to play a role in NPP. However, it remains unclear how AS cells and LPAR6 affect the occurrence and progression of NPP...