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The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.
Learn More >Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.
Learn More >Treatment options for chronic low back pain (CLBP) include cognitive behavioral interventions. Most of these interventions only have small and short-lived effects. Using strict inclusion criteria for participation in an intensive combined physical and psychological program, encouraging effects were reported at 1-year follow-up. This study evaluates the long-term follow-up results of the same program. The hypothesis is that previously reported results are maintained.
Learn More >Although C-C motif chemokine ligand 2 (CCL2) plays a critical role in the pathogenesis of neuropathic pain through neuron-microglia interactions, its pronociceptive function underlying inflammatory pain remains to be fully understood. The present study aimed to elucidate the potential role of CCL2 in pain sensitization following zymosan-induced inflammation. Intraplantar injection of zymosan into the rat hind paw significantly increased the expression of CCL2 in both dorsal root ganglions and the superficial dorsal horn. The expression of CCL2 was exclusively present in the isolectin B4-positive unmyelinated primary afferent fibers, but no in other cells of the spinal cord. Intrathecal administration of RS504393 (a CCR2 antagonist) markedly reduced the zymosan-induced thermal and mechanical hyperalgesia accompanied with reduced expression in the spinal cord of c-Fos, CD11b, phosphorylated p38 mitogen activated protein kinases (p-p38), and interleukin-1β. Whole cell patch-clamp recordings on spinal cord slices further revealed that the incubation of CCL2 evoked an evident inward current in substantia gelatinosa neurons and increased level of p-p38 in microglia. Moreover, co-incubation with minocycline (an inhibitor of microglial activation) prevented CCL2-mediated activation in the spinal cord slice. Taken together, we propose that the increased CCL2 expression from primary afferent fibers following zymosan-induced inflammation activates nociceptive neurons in the spinal dorsal horn via a microglia-dependent mechanism.
Learn More >Injury can lead to devastating and often untreatable chronic pain. While acute pain perception (nociception) evolved more than 500 million years ago, virtually nothing is known about the molecular origin of chronic pain. Here we provide the first evidence that nerve injury leads to chronic neuropathic sensitization in insects. Mechanistically, peripheral nerve injury triggers a loss of central inhibition that drives escape circuit plasticity and neuropathic allodynia. At the molecular level, excitotoxic signaling within GABAergic (γ-aminobutyric acid) neurons required the acetylcholine receptor and led to caspase-dependent death of GABAergic neurons. Conversely, disruption of GABA signaling was sufficient to trigger allodynia without injury. Last, we identified the conserved transcription factor twist as a critical downstream regulator driving GABAergic cell death and neuropathic allodynia. Together, we define how injury leads to allodynia in insects, and describe a primordial precursor to neuropathic pain may have been advantageous, protecting animals after serious injury.
Learn More >Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain.
Learn More >Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia.
Learn More >Persistent, in particular neuropathic pain affects millions of people worldwide. However, the response rate of patients to existing analgesic drugs is less than 50%. There are several possibilities to increase this response rate, such as optimization of the pharmacokinetic and pharmacodynamic properties of analgesics. Another promising approach is to use prognostic biomarkers in patients to determine the optimal pharmacological therapy for each individual. Here, we discuss recent efforts to identify plasma and CSF biomarkers, as well as genetic biomarkers and sensory testing, and how these readouts could be exploited for the prediction of a suitable pharmacological treatment. Collectively, the information on single biomarkers may be stored in knowledge bases and processed by machine-learning and related artificial intelligence techniques, resulting in the optimal pharmacological treatment for individual pain patients. We highlight the potential for biomarker-based individualized pain therapies and discuss biomarker reliability and their utility in clinical practice, as well as limitations of this approach.
Learn More >Chronic neuropathic pain constitutes a serious public health problem, but the disease mechanisms are only partially understood. The involvement of different brain regions like the medial prefrontal cortex has already been established, but the comparison of the role of different subregions and layers is still inconclusive. In the current study, we performed patch-clamp recordings followed by anatomical reconstruction of pyramidal cells from different layers of the prelimbic and infralimbic subregions of the medial prefrontal cortex in neuropathic (spared nerve injury, SNI) and control mice. We found that in the prelimbic cortex, layer 2/3 pyramidal cells from SNI mice exhibited increased excitability compared to sham controls, whereas prelimbic layer 5 pyramidal neurons showed reduced excitability. Pyramidal cells in both layer 2/3 and layer 5 of the infralimbic subregion did not change their excitability, but layer 2/3 pyramidal cells displayed increased dendritic length and branching. Our findings support the view that chronic pain is associated with subregion- and layer-specific changes in the medial prefrontal cortex. They therefore provide new insights into the mechanisms underlying the chronification of pain.
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