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Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here, we describe novel technology to selectively photoablate TrkA-positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near-infrared illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic, and joint pain. To target peripheral nociceptors, we generated a SNAP-tagged NGF derivative NGF that binds to TrkA/p75 receptors but does not provoke signaling in TrkA-positive cells or elicit pain behaviors in mice. NGF was coupled to the photosensitizer IRDye700DX phthalocyanine (IR700) and injected subcutaneously. After near-infrared illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic, and neuropathic pain, mechanical hypersensitivity was abolished for 3 weeks after a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then reinnervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGF-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.
Learn More >Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major toxicity of cancer treatment, leading to dose reduction and premature treatment cessation, potentially affecting patient function, and quality of life. The development of accurate and sensitive assessment tools for CIPN is essential to enable clinical monitoring during treatment, follow-up of long-term outcomes and measurement of toxicity in clinical trials. This review examines CIPN clinical assessment scales incorporating clinician-based, composite, and patient-reported outcomes (PROs), providing a systematic review of their properties and an updated critical analysis of recommendations on current evidence for their use. This systematic review of CIPN assessment tools identified 50 papers containing 41 assessment tools, across 4 categories (common toxicity criteria; composite neurological scale; PROs; pain scale). The majority of these tools were PROs, underscoring the importance of patient-based assessment of symptoms. While there has been considerable work in the field over the past 10 years, this review highlights significant gaps, including a lack of evaluation of responsiveness and problematic neuropathic pain evaluation. There remains a need for consensus on the best available tool and the need to modify existing instruments to improve utility.
Learn More >Painful Temporomandibular Disorder is Associated with Migraine in Adolescents: a case-control study.
Some types of primary headaches and temporomandibular disorders (TMD) are comorbid in adults and highly prevalent in adolescents. Herein, we investigated the association of painful TMD with specific headache diagnoses (migraine, tension-type headache) and with headache frequency in adolescents. We also explored the association of headache diagnosis with the number of painful sites in the trigeminal area. Painful TMD was assessed using the Research Diagnostic Criteria for TMD. We conducted a case-control study of adolescents from 13-15 years old who were recruited among participants in a previous epidemiological study conducted in Araraquara, SP, Brazil. Headaches were classified according to the Second Edition of the International Classification for Headache Disorders. Logistic, multinomial logistic and linear regression models were used to test associations. Of 149 individuals, 55.7% presented painful TMD. Adolescents with painful TMD (cases) were more likely to have migraine compared with those without TMD (controls) [OR= 3.0 (95% CI: 1.47-6.19); p=0.033]. Significant differences were not observed for probable TTH (p=0.307) and TTH (p=0.834). Painful TMD was also associated with an increase in headache frequency (linear-by-linear association=8.051; p=0.005). Only migraine was associated with a greater number of painful sites on palpation in the trigeminal area (p= 0.001). Migraine and frequency of headache were associated with painful TMD in adolescents. PERSPECTIVE: Migraine and headache frequency were strongly associated with painful TMD in adolescents, and causality must be determined. For now, the presence of one condition should raise suspicion of the other and warrants collaboration between orofacial pain specialists and neurologists.
Learn More >People who are especially afraid of pain may display attention biases that increase their risk for developing chronic pain following an injury. However, specific neurophysiological mechanisms underlying associations between elevated trait fear of pain levels and environmental cues that signal potential pain experiences are not well understood. To address this gap, event-related potentials (ERPs) were recorded among 39 high pain-fearful (H-FOP) and 36 low pain-fearful (L-FOP) adults exposed to potentially painful somatosensory stimulation cued by sensory pain words versus non-painful stimulation cued by neutral words. H-FOP group members displayed slower reaction times in judging somatosensory stimulation and rated stimulation to be more intense than L-FOP group members did. H-FOP group members also exhibited comparatively earlier peak latencies of P2 and N2 components during word cue presentations as well as weaker P3 amplitudes in processing non-painful stimulation cued by sensory pain words. These findings suggested that, among the high trait pain-fearful, exposure to word cues signaling potential pain results in the allocation of fewer cognitive resources towards processing somatosensory stimuli that are not actually painful. This article is protected by copyright. All rights reserved.
Learn More >Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab.
Learn More >Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a three-year follow-up to either a persistent or non-persistent pain phenotype, next generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the non-persistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine learning based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65 – 72 %. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype phenotype association.
Learn More >Injury associated pain involves subjective perception and emotional experience. The anterior cingulate cortex (ACC) is a key area involved in the affective component of pain processing. However, the neuroimmune mechanisms underlying enhanced ACC excitability following peripheral nerve injury are still not fully understood. Our previous work has shown that tumor necrosis factor-alpha (TNF-α) overexpression leads to peripheral afferent hyperexcitability and synaptic transmission potentiation in spinal cord. Here, we aimed to reveal the potential role of ACC TNF-α in ACC hyperexcitability and neuropathic pain. c-Fos, a widely used neuronal activity marker, was induced especially in contralateral ACC early [postoperative (PO) 1 h] and later (PO day 7 and 10) during the development of neuropathic pain. Spared nerve injury (SNI) elevated TNF-α level in contralateral ACC from PO day 5 to 14, delayed relative to decreased ipsilateral paw withdrawal threshold apparent from PO day 1 to 14. Microinjection of anti-TNF-α antibody into the ACC completely eliminated c-Fos overexpression and greatly attenuated pain aversion and mechanical allodynia induced by SNI, suggesting an important role of ACC TNF-α in the pain aversiveness and pain maintenance. Furthermore, modulating ACC pyramidal neurons via a Gi-coupled human M4 muscarinic receptor (hM4Di) or a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD), greatly changed the ACC TNF-α level and the mechanical paw withdrawal threshold. The positive interactions between TNF-α and ACC neurons might modulate the cytokine microenvironment thus contribute to the neuropathic pain.
Learn More >Epidemiological studies have shown an increased risk of cardiovascular events in migraineurs. The pathophysiological mechanisms of this observation remain largely unknown. Recent genetic and epidemiologic studies suggest, that atherosclerosis might be the overlapping pathophysiological mechanism in migraine and coronary heart disease. The aim of the present study was to evaluate if the increased cardiovascular risk in migraineurs is attributed to an increased coronary artery calcification. For this the coronary artery calcium score was assessed by computed tomography of the heart in 1.437 patients of which 337 were migraineurs. All patients had a similar cardiovascular risk profile, so that the risk for coronary calcifications could be considered similar between migraineurs and non-migraineurs. The results showed no significant differences in the amount of coronary calcifications in patients with or without migraine. This suggests that a more pronounced coronary artery calcification, as a surrogate marker of coronary atherosclerosis, does not underlie the increased cardiovascular risk in migraineurs. A distinct common pathophysiological mechanism in migraine and coronary heart disease such as endothelial dysfunction or vasospasm should be discussed instead. However, it has to be considered, that the coronary artery calcification score does not indicate the total risk of atherosclerotic changes in the coronary arteries.
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