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We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization following red light is observed in multiple body areas reminiscent of widespread pain in functional pain syndromes. Rats were exposed to red light emitting diodes (RLED) (LEDs, 660 nanometer) at an intensity of 50 Lux for 8 hours daily for 5 days resulting in time- and dose-dependent thermal hyperalgesia and mechanical allodynia in both male and female rats. Females showed earlier onset of mechanical allodynia than males. The pronociceptive effects of RLED were mediated through the visual system. RLED-induced thermal hyperalgesia and mechanical allodynia were reversed with medications commonly used for widespread pain including gabapentin, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and NSAIDs. Acetaminophen failed to reverse the RLED induced hypersensitivity. The hyperalgesic effects of RLED were blocked when bicuculline, a GABA-A receptor antagonist, was administered into the rostral ventromedial medulla (RVM) suggesting a role for increased descending facilitation in the pain pathway. Key experiments were subjected to a replication study with randomization, investigator-blinding, inclusion of all data and high levels of statistical rigor. RLED induced thermal hyperalgesia and mechanical allodynia without injury offers a novel injury free rodent model useful for the study of functional pain syndromes with widespread pain. RLED exposure also emphasizes the different biological effects of different colors light exposure. Perspective: This study demonstrates the effect of light exposure on nociceptive thresholds. These biological effects of red LED adds evidence to the emerging understanding of biological effects of light of different colors in animals and humans. Understanding the underlying biology of red light-induced wide spread pain may offer insights into functional pain states.
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1Tac1 nociceptor-MRGPRB2 mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
Most primary headaches can be diagnosed using the history and examination. Judicious use of neuroimaging and other testing, however, is indicated to distinguish primary headaches from the many secondary causes that may share similar features. This article evaluates the reasons for diagnostic testing and the use of neuroimaging, electroencephalography, lumbar puncture, and blood testing. The use of diagnostic testing in adults and children who have headaches and a normal neurologic examination, migraine, trigeminal autonomic cephalalgias, hemicrania continua, and new daily persistent headache are reviewed.
To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms.
To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares.
Evidence suggests there to be an association between chronic pain and disruption of the body schema. We tested the hypothesis in fibromyalgia syndrome.
Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN and TN can exist without a neurovascular contact. A common observation during microvascular decompression (MVD) surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology (PEA) to analyse the levels of 92 protein biomarkers related to inflammation in lumbar CSF from patients with TN (n=27) before and after MVD compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the CSF from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins appeared to be of specific interest for TN; TRAIL and TNF-β. Thus, inflammatory activity might be one important mechanism in TN.
Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain (CPP). Here we investigated the effects of linaclotide, an FDA approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium transplantation into the intestinal mesentery, rats developed endometrial lesions as well as vaginal hyperalgesia to distension and decreased mechanical hindpaw withdrawal thresholds. Daily oral administration of linaclotide, a peripherally restricted guanylate cyclase-C (GC-C) agonist peptide acting locally within the gastrointestinal tract increased pain thresholds to vaginal distension and mechanical hindpaw withdrawal thresholds relative to vehicle treatment. Furthermore, using a cross-over design, administering linaclotide to rats previously administered vehicle resulted in increased hindpaw withdrawal thresholds, whilst replacing linaclotide with vehicle treatment decreased hindpaw withdrawal thresholds. Retrograde tracing of sensory afferent nerves from the ileum, colon and vagina revealed that central terminals of these afferents lie in close apposition to one another within the dorsal horn of the spinal cord. We also identified dichotomizing dual-labelled ileal/colon innervating afferents as well as colon/vaginal dual-labelled neurons and a rare population of triple traced ileal/colon/vaginal neurons within thoracolumbar DRG. These observations provide potential sources of cross-organ interaction at the level of the DRG and spinal cord. GC-C expression is absent in the vagina and endometrial cysts suggesting that the actions of linaclotide are via shared nerve pathways between these organs. In summary, linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but concurrent treatment of comorbid CPP syndromes.
The cost of US health care continues to increase, with treatments related to low back and neck pain and other musculoskeletal disorders accounting for the third highest amount of various disease categories. Interventional techniques for managing pain apart from conservative modalities and surgical interventions, have generally been thought to be growing rapidly. However, a recent analysis of utilization of interventional techniques from 2000 to 2016 has shown a modest decline from 2009 to 2016, compared to 2000 to 2009.
It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.