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Nerve-binding fluorophores with near-infrared (NIR; 650 to 900 nm) emission could reduce iatrogenic nerve injury rates by providing surgeons precise, real-time visualization of the peripheral nervous system. Unfortunately, current systemically administered nerve contrast agents predominantly emit at visible wavelengths and show nonspecific uptake in surrounding tissues such as adipose, muscle, and facia, thus limiting detection to surgically exposed surface-level nerves. Here, a focused NIR fluorophore library was synthesized and screened through multi-tiered optical and pharmacological assays to identify nerve-binding fluorophore candidates for clinical translation. NIR nerve probes enabled micrometer-scale nerve visualization at the greatest reported tissue depths (~2 to 3 mm), a feat unachievable with previous visibly emissive contrast agents. Laparoscopic fluorescent surgical navigation delineated deep lumbar and iliac nerves in swine, most of which were invisible in conventional white-light endoscopy. Critically, NIR oxazines generated contrast against all key surgical tissue classes (muscle, adipose, vasculature, and fascia) with nerve signal-to-background ratios ranging from ~2 (2- to 3-mm depth) to 25 (exposed nerve). Clinical translation of NIR nerve-specific agents will substantially reduce comorbidities associated with surgical nerve damage.
Learn More >Craniofacial muscle pain is highly prevalent in temporomandibular disorders but is difficult to treat. Enhanced understanding of neurobiology unique to craniofacial muscle pain should lead to the development of novel mechanism-based treatments. Herein, we review recent studies to summarize neural pathways of craniofacial muscle pain. Nociceptive afferents in craniofacial muscles are predominantly peptidergic afferents enriched with TRPV1. Signals from peripheral glutamate receptors converge onto TRPV1, leading to mechanical hyperalgesia. Further studies are needed to clarify whether hyperalgesic priming in nonpeptidergic afferents or repeated acid injections also affect craniofacial muscle pain. Within trigeminal ganglia, afferents innervating craniofacial muscles interact with surrounding satellite glia, which enhances the sensitivity of the inflamed neurons as well as nearby uninjured afferents, resulting in hyperalgesia and ectopic pain originating from adjacent orofacial tissues. Craniofacial muscle afferents project to a wide area within the trigeminal nucleus complex, and central sensitization of medullary dorsal horn neurons is a critical factor in muscle hyperalgesia related to ectopic pain and emotional stress. Second-order neurons project rostrally to pathways associated with affective pain, such as parabrachial nucleus and medial thalamic nucleus, as well as sensory-discriminative pain, such as ventral posteromedial thalamic nuclei. Abnormal endogenous pain modulation can also contribute to chronic muscle pain. Descending serotonergic circuits from the rostral ventromedial medulla facilitate activation of second-order neurons in the trigeminal nucleus complex, which leads to the maintenance of mechanical hyperalgesia of inflamed masseter muscle. Patients with temporomandibular disorders exhibit altered brain networks in widespread cortical and subcortical regions. Recent development of methods for neural circuit manipulation allows silencing of specific hyperactive neural circuits. Chemogenetic silencing of TRPV1-expressing afferents or rostral ventromedial medulla neurons attenuates hyperalgesia during masseter inflammation. It is likely, therefore, that further delineation of neural circuits mediating craniofacial muscle hyperalgesia potentially enhances treatment of chronic muscle pain conditions.
Learn More >Migraine, and especially migraine with aura, is associated with an increased risk of stroke and vascular events; however, the reasons for this association are unclear. Several studies evaluated cerebral autoregulation and vasomotor reactivity in patients with migraine compared with non-migraineurs, with conflicting results. Our narrative review aimed at summarizing their results to find the most reliable evidence in the field. Studies which used visual stimuli to evoke vascular responses consistently showed an increased vascular reactivity in migraineurs compared with non-migraineurs, while studies which used systemic stimuli such as hyper- or hypocapnia showed inconsistent results. Therefore, central neural mechanisms might be more important than peripheral vascular mechanisms in determining the cerebral vascular responses of patients with migraine. However, a large body of evidence supports the existence of peripheral vascular dysfunction in patients with migraine. Further studies are needed to explain the complex interactions between central neural and peripheral vascular mechanisms in determining migraine and its vascular risk. Migraine preventive treatments, and especially the most recent ones with a peripheral action, might provide important insights in this field.
Learn More >High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end-product specific receptor (receptor for advanced glycation end-products; RAGE) or Toll-like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, dramatically promote thrombin-dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1-dependent pathological pain. Small molecules that directly inactivate HMGB1 or antagonize HMGB1-targeted receptors would be useful to reduce various intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain.
Learn More >Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.
Learn More >To estimate the effects of excess body mass and leisure time physical activity on the incidence and persistence of chronic pain.
Learn More >Recently the voltage-gated sodium (Nav) channels began to be studied as possible targets for analgesic drugs. In addition, specific Nav 1.8 blockers are currently being used to treat some types of chronic pain pathologies such as neuropathies and fibromyalgia. Nav 1.8 fibers convey nociceptive information to brain structures belonging to the limbic system, which is involved in the pathophysiology of major depressive disorders. From this, using a model of chronic social defeat stress (SDS) and intrathecal injections of Nav 1.8 antisense, this study investigated the possible involvement of Nav 1.8 nociceptive fibers in SDS- induced hyperalgesia in C57/BL mice. Our results showed that SDS induced a depressive-like behavior of social avoidance and increased the sensitivity to mechanical (electronic von Frey test) and chemical (capsaicin test) nociceptive stimuli. We also showed that intrathecal injection of Nav 1.8 antisense reversed the SDS-induced hyperalgesia as demonstrated by both, mechanical and chemical nociceptive tests. We confirmed the antisense efficacy and specificity in a separate no-defeated cohort through real-time PCR, which showed a significant reduction of Nav 1.8 mRNA and no reduction of Nav 1.7 and Nav 1.9 in the L4, L5 and L6 dorsal root ganglia (DRG). The present study advances the understanding of SDS-induced hyperalgesia, which seems to be dependent on Nav 1.8 nociceptive fibers.
Learn More >To determine the perceived benefits of in older adults with chronic low-back pain (cLBP). A qualitative analysis from a randomized controlled feasibility trial. Eighteen participants (65+ years old) with cLBP of at least moderate intensity. A 36-week intervention beginning with twice weekly classes for 12 weeks, weekly classes for 6 weeks, biweekly classes for 6 weeks, and monthly classes for 12 weeks. Participants were asked to practice at home on nonclass days and videos were provided to assist in that process. Participants in the focus groups were asked to provide feedback on their experiences with the study as well as the benefits of their practice. We used demographic and class attendance data to describe the sample. Regarding the benefits of practice, five major themes were identified: functional benefits, pain reduction/pain relief, psychospiritual benefits, the importance of social support in learning , and the integration of into daily activities. The most common functional benefits were improvements in balance, flexibility, leg strength, and posture. Some reported pain reduction or pain relief, but others did not. Increased relaxation, mindfulness, and a sense of connectedness were subthemes that emerged from psychospiritual benefits. Social support benefits included motivation to attend class and group support while learning a new skill. Finally, improved body awareness allowed participants to integrate skills into their daily activities. This qualitative analysis demonstrates the multifaceted benefits of for older adults living with cLBP.
Learn More >Neck pain commonly accompanies recurrent headaches such as migraine, tension-type and cervicogenic headache. Neck pain may be part of the headache symptom complex or a local source. Patients commonly seek neck treatment to alleviate headache, but this is only indicated when cervical musculoskeletal dysfunction is the source of pain. Clinical presentation of reduced cervical extension, painful cervical joint dysfunction and impaired muscle function collectively has been shown to identify cervicogenic headache among patients with recurrent headaches. The pattern's validity has not been tested against the 'gold standard' of controlled diagnostic blocks. This study assessed the validity of this pattern of cervical musculoskeletal signs to identify a cervical source of headache and neck pain, against controlled diagnostic blocks, in patients with headache and neck pain.
Learn More >Background: Patients with chronic pain often have limited access to comprehensive care that includes behavioral pain management strategies. Virtual reality (VR) is an immersive technology and emerging digital behavioral pain therapeutic with analgesic efficacy for acute pain. We found no scientific literature on skills-based VR behavioral programs for chronic pain populations.
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