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Pulmonary vagal nociceptors defend the airways. Cardiopulmonary vagal nociceptors synapse in the nucleus tractus solitarius (NTS). Evidence has demonstrated convergence of cardiopulmonary nociceptors with afferents from carotid chemoreceptors. Whether sensory convergence occurs in motor nuclei and how sensory convergence affects reflexive efferent motor output directed towards the airways are critical knowledge gaps. Here we show that distinct tracer injection into the pulmonary nociceptors and carotid chemoreceptors lead to co-labelled neurons in the nucleus tractus solitarius and nucleus ambiguus. Precise simultaneous stimulation delivered to pulmonary nociceptors and carotid chemoreceptors doubled efferent vagal output, enhanced phrenic pause and subsequently augmented phrenic motor activity. These results suggest that multiple afferents are involved in protecting the airways and concurrent stimulation enhances airway defensive reflex output.
Learn More >: Purinergic receptors play a critical role in neurotransmission, and modulation of complex physiological functions. As such, they have been implicated in numerous disease states including chronic pain, inflammation, autoimmune disease, and cancer. The past decade has seen substantial progress in the design of novel chemical compounds that act on the P2X class of receptors and warrants an updated review of this field.
Learn More >An ACVR1 activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.
Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the bone morphogenetic protein (BMP) type I receptor ACVR1 (ACVR1R206H), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although FOP patients can harbor pathological lesions in the peripheral and central nervous system, their etiology is unclear. Quantitative Sensory Testing (QST) of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major impact of ACVR1R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells (iPSCs), both intracellular and extracellular electrophysiology analysis of the ACVR1R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.
Learn More >The hypermobile type of Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder, associated with joint hypermobility and prominent chronic pain. Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood.
Learn More >The composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration.
Learn More >Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.
Learn More >Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study.
Migraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine.
Learn More >Quantitative Sensory Testing (QST) is used to test somatosensory functioning in patients with low back pain (LBP) and most performed on people with chronic LBP in secondary/tertiary health care facilities. Studies using QST-testing on LBP populations in primary care are scarce. Central Sensitization Inventory (CSI) measures central sensitization (CS)-related symptoms and studies investigating the differences between QST-testing and participants with LBP with a positive and negative score on the CSI questionnaire are also rare. This case-control study investigates differences of an extensive QST-measurement between patients with acute, chronic LBP and healthy controls in primary care. Secondary aim is to investigate differences of an extensive QST-measurement between "CS" and "no-CS" group.
Learn More >Trigeminal neuralgia (TN) is a rare but debilitating disorder characterized by excruciating facial pain, with a higher incidence in women. Recent studies demonstrated that TN patients present mutations in the gene encoding the CaV3.2 T-type calcium channel, an important player in peripheral pain pathways. Here we characterize the role of CaV3.2 channels in TN at two levels. First, we examined the biophysical properties of CACNA1H variants found in TN patients. Second, we investigated the role of CaV3.2 in an animal model of trigeminal neuropathic pain. Whole cell patch clamp recordings from four different mutants expressed in tsA-201 cells (E286K in the pore loop of domain I, H526Y, G563R and P566T in the domain I-II linker) identified a loss-of-function in activation in the E286K mutation and gain-of-function in the G563R and P566T mutations. Moreover, a loss-of-function in inactivation was observed with the E286K and H526Y mutations. Cell surface biotinylation revealed no difference in channel trafficking among the variants. The G563R mutant also caused a gain-of-function in the firing properties of transfected trigeminal ganglion neurons. In female and male mice, constriction of the infraorbital nerve (CION) induced facial thermal heat hyperalgesia. Block of T-type channels with Z944 resulted in antihyperalgesia. The effect of Z944 was absent in CaV3.2-/- mice, indicating that CaV3.2 is the molecular target of the antihyperalgesic Z944 effect. Finally, ELISA analysis revealed increased CaV3.2 channel expression in the spinal trigeminal subnucleus caudalis. Altogether, the present study demonstrates an important role of CaV3.2 channels in trigeminal pain.
Learn More >Pain and related disability remain a major social and therapeutic problem. Comorbidities and therapies increase drug interactions and side effects making pain management more compounded especially in the elderly who are the fastest-growing pain population. Multimodal analgesia consists of using two or more drugs and/or techniques that target different sites of pain, increasing the level of analgesia and decreasing adverse events from treatment. Paracetamol enhances multimodal analgesia in experimental and clinical pain states. Strong preclinical evidence supports that paracetamol has additive and synergistic interactions with anti-inflammatory, opioid and anti-neuropathic drugs in rodent models of nociceptive and neuropathic pain. Clinical studies in young and adult elderly patients confirm the utility of paracetamol in multimodal, non-opioid or opioid-sparing, therapies for the treatment of acute and chronic pain.
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