Voltage-gated potassium channel subfamily q member 4 (Kcnq4) is predominantly expressed by hair cells and auditory neurons and regulates the neuronal excitability in the auditory pathway. Although it is further detected in myelinated large-diameter dorsal root ganglia (DRG) neurons in the periphery, the expression and function of Kcnq4 channel in nociceptors remains unknown. Here we showed that Kcnq4

Advancements in clinical science have shown the necessity for a paradigm shift away from a biomedical toward a biopsychosocial approach. Yet, the translation from clinical science into clinical practice is challenging. The aim of this study was to assess the short-term and mid-term changes in pain knowledge and attitudes and guideline-adherent recommendations of healthcare professionals (HCP) by means

There is growing acceptance for combining complementary and integrative health (CIH) therapies with standard rehabilitative care (SRC) for chronic pain management, yet little evidence on the best sequence of therapies. We investigated whether starting with CIH therapies or SRC is more effective in reducing pain impact. Participants were 280 service members with predominantly (88%) musculoskeletal chronic

In phase II clinical trials, NaV1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and NaV1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we

A pain inequity exists for Native Americans (NAs), but the mechanisms are poorly understood. The Oklahoma Study of Native American Pain Risk (OK-SNAP) addressed this issue and recruited healthy, pain-free NAs and non-Hispanic Whites (NHWs) to attend 2 laboratory visits and assessed mechanisms consistent with the biopsychosocial model of pain: demographics, physical variables, psychosocial factors,

Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been

Evidence linking adverse childhood experiences and chronic pain in adulthood is largely cross-sectional, potentially subject to recall bias and does not allow exploration of mediating pathways. We analysed a large population-based cohort (UK Biobank) using a causal framework, to determine if childhood maltreatment is related to chronic "all over" body pain in adulthood. We used doubly robust estimation

Spinal cord injury (SCI) results in permanent neurological dysfunction and neuropathic pain. To address this pathology, we recently conducted a clinical study in which we transplanted neural precursor cells (NPCs) derived from human induced pluripotent stem cells into patients during the subacute phase of SCI. One of the therapeutic mechanisms of cell transplantation is the formation of synaptic connections

Improving health and wellbeing outcomes for people experiencing chronic musculoskeletal pain requires collective efforts across multiple levels of a healthcare ecosystem. System-wide barriers to care equity must however be addressed (eg, lack of co-designed services; overuse of low value care/underuse of high value care; inadequate health workforce; inappropriate funding models; inequitable access

Nociplastic pain, a third mechanistic pain descriptor in addition to nociceptive and neuropathic pain, was adopted in 2017 by the International Association for the Study of Pain (IASP). It is defined as "pain that arises from altered nociception" not fully explained by nociceptive or neuropathic pain mechanisms. Peripheral and/or central sensitization, manifesting as allodynia and hyperalgesia, is

The burden of pain in low- and middle income countries (LMICs) is high and expected to rise further with their ageing populations. Multidisciplinary pain management approaches based on the biopsychosocial model of pain have been shown to be effective in reducing pain-related distress and disability, but these approaches are still lacking in many LMICs due to various factors, including low levels of

The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)- appraisals of pain as threatening, overwhelming, and unmanageable- and review the evidence that these thoughts

Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called "neuroinflammation" in human pain has been an object of contention for decades. Here, I present the results of multiple positron emission tomography (PET) studies measuring the levels

Forty-five years ago, Patrick Wall published his John J Bonica lecture "On the relation of injury to pain."90 In this lecture, he argued that pain is better classified as an awareness of a need-state than as a sensation. This need state, he argued, serves more to promote healing than to avoid injury. Here I reframe Wall's prescient proposal to pain in early life and propose a set of different need

While our understanding of pain is rapidly growing, some areas of pain research are lagging behind. This article discusses two current and inter-related gaps in knowledge that are in need of addressing: first, the connections between "brain" and "body" components of pain; and second, the process of endogenous pain resolution. Historical reasons for these research gaps are discussed and solutions are

People with special needs, like those with Down syndrome, Parkinson disease, or dementia, frequently suffer from orofacial pain conditions and dysfunction of the masticatory system. However, the accurate assessment of orofacial pain and dysfunction in such individuals is challenging. In this review, the complexities of assessing and managing orofacial pain and dysfunction in special needs populations

"Somehow scientists still pursue the same questions, if now on higher levels of theoretical abstraction rooted in deeper layers of empirical evidence… To paraphrase an old philosophy joke, science is more like it is today than it has ever been. In other words, science remains as challenging as ever to human inquiry. And the need to communicate its progress… remains as essential now as then." - Tom

Developmental trajectories for neck disability after whiplash injury have been identified. Their relationship to cold and mechanical sensitivity trajectories is not known. We aimed to (1) identify recovery trajectories of cold and mechanical sensitivity, (2) explore their codevelopment with disability trajectories, (3) identify predictors of sensitivity trajectories, and (4) explore codevelopment of

The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection

Research has shown that pain and sleep disturbance often co-occur and influence each other over time in children and adolescents with chronic pain. Longitudinal studies examining the underlying mechanisms of this association are scarce and have focused primarily on the role of internalizing mental health symptoms and mood. This longitudinal study aimed to determine whether fatigue underlies the co-occurrence

Although opioids continue to be used internationally for noncancer pain, evidence to date on the comparative safety of different opioids is sparse and conflicting. The aim of this study was to examine the comparative risk of all-cause mortality in patients newly initiated on opioids for noncancer pain, across 3 jurisdictions in the United Kingdom (UK), United States, and Canada. A multicentre retrospective

We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants

The nociceptive withdrawal reflex (NWR) is a spinal withdrawal reflex induced by painful stimulation. It is a measure of spinal hyperexcitability, which is believed to contribute to chronic musculoskeletal pain (MSKP) and headache. Previous syntheses of the evidence for alterations in the NWR in patients with chronic MSKP and headache needed a comprehensive update. This systematic review and meta-analysis

The peripheral inflammatory response is an attractive therapeutic target for pain treatment. Neutrophils are the first circulating inflammatory cells recruited to sites of injury, but their contribution to pain outcomes is unclear. We performed a systematic review and meta-analysis of original preclinical studies, which evaluated the effect of preemptive neutrophil depletion on pain outcomes (PROSPERO

Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both peripheral and central sensitization, critical components of neuropathic pain. This study explores the role of the G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in the peripheral mechanisms underlying neuropathic pain induced

The voltage-gated sodium channel NaV1.7 plays an important role in pain processing according to genetic data. Those data made NaV1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, NaV1.7-selective inhibitors have

Chronic musculoskeletal pain (CMP) and coexisting mental health conditions impact young people; however, little is known about their lived and care experiences. In a prospectively registered systematic review with qualitative evidence synthesis (PROSPERO: CRD42022369914), we explored the following: (1) lived physical, psychological, and social experiences; and (2) care experiences/preferences of young

Nociceptors with somata in dorsal root ganglia (DRGs) readily switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Spontaneous activity (SA) during this state is present in vivo in rats months after spinal cord injury (SCI) and has been causally linked to SCI pain. Intrinsically generated SA and, more

In this randomized, double-blind, parallel placebo-controlled clinical trial, we evaluated the efficacy of methadone as an add-on therapy for people with chronic neuropathic pain (NP). Eighty-six patients were randomly assigned to receive methadone or placebo for 8 weeks. The primary outcome was the proportion of participants achieving at least 30% pain relief from baseline using a 100-mm pain Visual

Visual exposure to dim, green, light has been found to reduce pain levels in patients living with migraine, low back pain, and fibromyalgia. Preclinical studies discovered that the analgesic effect of green light was due to the central release of endogenous opioids and a reduction in inflammatory cytokines in the cerebrospinal fluid. The present study assessed the effect of green light therapy (GLT)

A recent Lancet Commission raised concerns about the management of child and adolescent pain. We aimed to undertake a comprehensive review of qualitative research to understand children and adolescent pain experiences across contexts. We used the 7 stages of meta-ethnography to synthesise findings. We combined the strengths of arts-based methods, translating themes into poems in a range of languages

Pain perception is closely tied to the brain's anticipatory processes, particularly involving the suppression of sensorimotor α-oscillations, which reflect the system's readiness for incoming pain. Higher sensorimotor α-oscillation levels are correlated with lower pain sensitivity. Alpha transcranial alternating current stimulation (α-tACS) can enhance these oscillations, potentially reducing pain

The effect of chronic pain on brain-predicted age is unclear. We performed secondary analyses of a large cross-sectional and 3-year longitudinal data set from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network to test the hypothesis that chronic pelvic pain accelerates brain aging and brain aging rate. Brain-predicted ages of 492 chronic pelvic pain patients and 72

Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across

We developed the SupportPrim PT clinical decision support system (CDSS) using the artificial intelligence method case-based reasoning to support personalised musculoskeletal pain management. The aim of this study was to evaluate the effectiveness of the CDSS for patients in physiotherapy practice. A cluster randomised controlled trial was conducted in primary care in Norway. We randomised 44 physiotherapists

Urocortin 3 is a neuropeptide that belongs to the corticotropin-releasing hormone family and is involved in mechanosensation and stress regulation. In this study, we show that Urocortin 3 marks a population of excitatory neurons in the mouse spinal cord, divided into 2 nonoverlapping subpopulations expressing protein kinase C gamma or calretinin/calbindin 2, populations previously associated with mechanosensation

Chemotherapy-induced peripheral neuropathic pain aggravates cancer survivors' life burden. Electroacupuncture (EA) has exhibited promising analgesic effects on neuropathic pain in previous studies. We investigated whether EA was effective in a paclitaxel-induced neuropathic pain mouse model. We further explored the functional role of astrocytes in the rostral ventromedial medulla (RVM), a well-established

Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other

Lower socioeconomic position (SEP) is associated with increased risk of developing chronic pain, experiencing more severe pain, and suffering greater pain-related disability. However, SEP is a multidimensional construct; there is a dearth of research on which SEP features are most strongly associated with high-impact chronic pain, the relative importance of SEP predictive features compared to established

Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human

Treating bone cancer pain (BCP) continues to be a clinical challenge, and the underlying mechanisms of BCP remain elusive. This study reports that Wnt5a/Ryk signaling in the dorsal root ganglion neurons is critical to the development of BCP. Tibia bone cavity tumor cell implantation produces spontaneous and evoked behaviorally expressed pain as well as ectopic sprouting and activity of Wnt5a/Ryk signaling

The sodium-activated potassium channel Slack (KNa1.1, Kcnt1) plays a critical role in tuning neuronal excitability. Previous studies have revealed that Slack is expressed in neurons of the superficial dorsal horn of the spinal cord. However, the precise role of Slack in spinal dorsal horn neurons is unclear. In this study, we used mice in which Slack is conditionally ablated in spinal dorsal horn neurons

The 2 tetrodotoxin-resistant (TTXr) voltage-gated sodium channel subtypes NaV1.8 and NaV1.9 are important for peripheral pain signaling. As determinants of sensory neuron excitability, they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and the release of neurotransmitters from sensory neuron terminals. NaV1.8 and NaV1.9, which are encoded

The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor

Understanding the development of chronic pain (CP) is challenging due to its multifactorial etiology. Child maltreatment (CM), encompassing various types of neglect and abuse affecting more than one-third of the population, is a critical aspect of early-life adversity with long-lasting impacts. It is increasingly recognized for its role in altering biopsychosocial processes, potentially increasing

There is a limited understanding of risk factors and comorbidities in trigeminal neuralgia, a disease characterized by paroxysms of severe unilateral facial pain and a higher incidence in women. We aim to identify temporally associated comorbidities involving trigeminal neuralgia by analyzing nationwide disease trajectories. Using data from 7.2 million unique individuals in the Danish National Patient

Patients with temporomandibular disorders (TMDs) typically experience facial pain and discomfort or tenderness in the temporomandibular joint (TMJ), causing disability in daily life. Unfortunately, existing treatments for TMD are not always effective, creating a need for more advanced, mechanism-based therapies. In this study, we used in vivo GCaMP3 Ca2+ imaging of intact trigeminal ganglia (TG) to

Neuropathic pain is a debilitating chronic condition that remains difficult to treat. More efficacious and safer therapeutics are needed. A potential target for therapeutic intervention recently identified by our group is the G-protein coupled receptor 160 (GPR160) and the cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand for GPR160. Intrathecal administration of CARTp in rodents

Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve

Neuroimaging-based pain biomarkers, when combined with machine learning techniques, have demonstrated potential in decoding pain intensity and diagnosing clinical pain conditions. However, a systematic evaluation of how different modeling options affect model performance remains unexplored. This study presents the results from a comprehensive literature survey and benchmark analysis. We conducted a

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid

As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and

Nav1.9 is of interest to the pain community for a number of reasons, including the human mutations in the gene encoding Nav1.9, SCN11a, that are associated with both pain and loss of pain phenotypes. However, because much of what we know about the biophysical properties of Nav1.9 has been learned through the study of rodent sensory neurons, and there is only 76% identity between human and rodent homologs