Open research questions in Pain Mechanisms and Treatments

What the literature leaves open

• Investigating the mechanisms of attentional regulation of immune responses, - Examining the effects of attention on other physiological processes, - Studying the relationship between attention and immune function in different populations

  Voluntary attention regulates acute immune responses in humans · 2026 · DOI

• Mechanism-informed stratification integrating synovitis imaging, soluble biomarkers, quantitative sensory testing, and clinical pain features may help distinguish inflammatory, structural, and nociplastic contributions

  Neuroimmune crosstalk in osteoarthritis pain: from synovial inflammation to pain sensitization · 2026 · DOI

• Further studies are needed to confirm the findings, - Research on the pathogenesis of DPN is ongoing, - The role of exosomes in the pathogenesis of DPN needs further investigation

  Blood-activating and collateral-unblocking traditional Chinese medicine formulas combined with mecobalamin for peripheral neuropathy in type 2 diabetes: a systematic review and Bayesian network meta-analysis · 2026 · DOI

• Investigate the involvement of VGCCs in cold pain-induced DRG calcium transients, - Explore the use of other models to capture the in vivo response to cold pain

  Voltage-gated sodium channel, Nav 1.8, regulates calcium dynamics in the dorsal root ganglion induced by cold nociceptive stimulus · 2026 · DOI

• Ex vivo experiments cannot sufficiently replicate the noxious cold sensing that occurs in vivo. The in vivo response to cold pain has not been previously captured via imaging of the Thy1-GCaMP6f mouse model.

  Voltage-gated sodium channel, Nav 1.8, regulates calcium dynamics in the dorsal root ganglion induced by cold nociceptive stimulus · 2026 · DOI

• The lack of universally accepted objective indicators for pain management and treatment. Limited understanding of the genetic correlations and causal relationships between brain imaging-derived phenotypes and site-specific pain. The need for further advancements in the fundamental mechanisms of pain.

  Brain imaging-wide exploration of site-specific pain: genetic correlation and Mendelian randomization study · 2026 · DOI

• Third, although in vitro experiments confirmed microglial phagocytic capacity and Axl’s role in maintaining this function, its regulatory network remains unclear. Previous studies have reported that AXL kinase-mediated astrocytic phagocytosis influences outcomes after traumatic brain injury57; however, the role of astrocytic Axl in the progression of neuropathic pain remains to be elucidated. and pain modulation, the relative contribution of Axl expressed in other cell types to these phenotypes cannot be excluded and warrants further investigation. These functional differences may be associated with distinct microglial subtypes or variations in phagocytic receptors, which warrants further investigation in future studies. Importantly, the function of Axl in chronic neuropathic pain is likely not limited to a simple ligand–receptor interaction.

  Integrated analysis of single-cell and transcriptome data reveals temporal dynamics of microglial phagocytic reprogramming in neuropathic pain progression · 2026 · DOI

• Investigate the impact of psychosocial factors on chronic pain mechanisms. Develop more accurate diagnostic tools for distinguishing between neuropathic and nociplastic pain.

  Proposal to refine the mechanistic classification of chronic pain and corresponding clinical symptomatology · 2026 · DOI

• The current classification does not accurately reflect the underlying mechanisms of chronic pain. There is a need for a more comprehensive understanding of the mechanisms of chronic pain.

  Proposal to refine the mechanistic classification of chronic pain and corresponding clinical symptomatology · 2026 · DOI

• The actual prevalence of dysautonomia in musculoskeletal conditions remains unknown. The associations between pain severity, psychological factors, and dysautonomia severity are not well understood.

  Prevalence of dysautonomia in chronic musculoskeletal pain: a cross-sectional study · 2026 · DOI

• elucidating the full extent of DRG-S mechanisms necessitates further exploration, particularly regarding its supraspinal effects and its interactions with cognitive and affective networks

  Mechanisms of Action of Dorsal Root Ganglion Stimulation · 2024 · DOI

• The precise mechanisms underlying DRG-S-induced analgesia remain elusive - The supraspinal effects of DRG-S are not well understood - The interactions between DRG-S and cognitive and affective networks are not well understood

  Mechanisms of Action of Dorsal Root Ganglion Stimulation · 2024 · DOI

• Most of the current information about the LC in human beings is based on post-mortem anatomical and mammalian studies - Statements about LC stem from animal model studies, and their clinical implications should be taken carefully - The exact mechanisms involved in the LC functional shift remain unknown

  The Locus Coeruleus in Chronic Pain · 2024 · DOI

• Further research is needed to understand the exact mechanisms involved in the LC functional shift - Studies on human subjects are necessary to confirm the findings from animal models - Research on the role of the LC in the development and maintenance of chronic pain is needed

  The Locus Coeruleus in Chronic Pain · 2024 · DOI

• Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited.

  NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease · 2026 · DOI

• Tac1-lineage neurons in the spinal dorsal horn have been implicated in coping behavior in response to sustained noxious stimuli, but their developmental origin, cellular heterogeneity, and functional contribution remain incompletely understood.

  Superficial spinal Tac1-lineage neurons are polymodal nociceptive · 2026 · DOI

• These findings provide potential molecular targets and pathways for further investigation into the pathophysiology of fibromyalgia.

  Network-Based Analysis of Fibromyalgia-Associated Genes Identifies Candidate Molecular Targets and Enriched Biological Pathways · 2026 · DOI

• Despite its prevalence, effective treatment options are limited and the underlying pathophysiological mechanisms are not fully understood.

  Network-Based Analysis of Fibromyalgia-Associated Genes Identifies Candidate Molecular Targets and Enriched Biological Pathways · 2026 · DOI

• The functional evolution of microglia during pain chronification is poorly understood. The mechanisms driving the transition from acute to chronic neuropathic pain remain unclear. The role of microglial phagocytic function in neuropathic pain progression is not well understood.

  Integrated analysis of single-cell and transcriptome data reveals temporal dynamics of microglial phagocytic reprogramming in neuropathic pain progression · 2026 · DOI

• However, somatosensory abnormalities in drug‐naïve PD remain insufficiently characterized, particularly in the absence of dopaminergic medication effects.

  Early Pain and Sensory Dysfunction in Drug‐Naïve Parkinson's Disease: Evidence From Quantitative Sensory Testing · 2026 · DOI

• The mechanisms by which psychological stress increases postoperative pain, especially in women, remain unknown.

  A prolactin-targeting antibody to prevent stress-induced peripheral nociceptor sensitization and female postoperative pain · 2025 · DOI

• Neuropathic pain involves complex cortical mechanisms, yet the role of the medial secondary visual cortex (V2M) remains poorly understood.

  A glutamatergic innervation from medial area of secondary visual cortex to lateral posterior thalamic nucleus facilitates nociceptive and neuropathic pain · 2025 · DOI

• However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear.

  Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation · 2024 · DOI

• As an essential part of the neuroimmune system, astrocytes that represent about 40–50% of glia cells within the central nervous system, are required for physiological neuronal functions, but their role in the amygdala remains to be determined for pain conditions.

  Impaired amygdala astrocytic signaling worsens neuropathic pain-associated neuronal functions and behaviors · 2024 · DOI

• While amygdala neuroplasticity has been linked causally to pain behaviors, non-neuronal pain mechanisms in this region remain to be explored.

  Impaired amygdala astrocytic signaling worsens neuropathic pain-associated neuronal functions and behaviors · 2024 · DOI

Most-cited papers in Pain Mechanisms and Treatments

• Pain Mechanisms: A New Theory · Science · 1965 · 8,981 citations
• The inflammatory reflex · Nature · 2002 · 3,183 citations
• Empathy for Pain Involves the Affective but not Sensory Components of Pain · Science · 2004 · 3,030 citations
• Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor · Science · 2000 · 3,029 citations
• Neuronal Plasticity: Increasing the Gain in Pain · Science · 2000 · 2,991 citations
• The biopsychosocial approach to chronic pain: Scientific advances and future directions. · Psychological Bulletin · 2007 · 2,708 citations
• Pain Affect Encoded in Human Anterior Cingulate But Not Somatosensory Cortex · Science · 1997 · 2,114 citations
• Molecular mechanisms of nociception · Nature · 2001 · 2,077 citations
• Neuropathic pain: aetiology, symptoms, mechanisms, and management · The Lancet · 1999 · 1,706 citations
• Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes Mellitus<SUBTITLE>A Randomized Controlled Trial</SUBTITLE> · JAMA · 1998 · 1,220 citations

Most recent work

• Molecular architecture of human dermal sleeping nociceptors · Cell · 2026
• Diabetic Peripheral Neuropathy: Mechanisms and Emerging Therapies · Biology · 2026
• Fast-conducting mechanonociceptors uniquely engage reflexive and affective pain circuitry to drive protective responses · bioRxiv · 2026
• Midbrain somatostatin-expressing cells control pain-suppression during defensive states · bioRxiv · 2026
• Fu's subcutaneous needling therapy significantly enhances pain relief in sciatica rats by promoting mitochondrial autophagy · Biomedical Journal · 2026
• Synaptic-immune interactions in neuropathic pain: complement-mediated remodeling of spinal dorsal horn microcircuits · Frontiers in Cell and Developmental Biology · 2026
• Why pain biomarkers cannot replace the patient experience · Nature Neuroscience · 2026
• Multi-timescale dynamics organize descending pain modulation · bioRxiv · 2026
• Noninvasive and Objective Near Real-Time Detection of Pain Changes During Tonic Fluctuating Noxious Heat Stimulation · bioRxiv · 2026
• Neurofeedback of somatosensory alpha oscillations modulates sensory and affective pain through dissociable neurocognitive pathways · Pain · 2026

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