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The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.
Learn More >Central sensitisation is considered to have a pathophysiological role in chronic low back pain (LBP). Whether individuals with increased central sensitisation early in their condition are more likely to develop persistent pain or whether it increases over time is unclear. This study aimed to determine whether sensory profiles during acute LBP differ between individuals who did and did not recover by 6-months and to identify subgroups associated with outcomes. Individuals with acute LBP (<2 weeks of onset, N=99) underwent pain threshold (heat/cold/pressure) and conditioned pain modulation (CPM) testing after completing questionnaires related to pain/disability, sleep, and psychological status. Sensory measures were compared during the acute phase (baseline) and longitudinally (baseline/6-months) between unrecovered (≥pain and disability), partially recovered (<pain and/or disability), and recovered (no pain and disability) participants at 6-months. We assessed baseline patterns of sensory sensitivity alone, and with psychological and sleep data, using hierarchical clustering and related the clusters to outcome (pain/disability) at 3- and 6-months. No sensory measure at either time-point differed between groups. Two subgroups were identified that associated with more ("high sensitivity") or less ("high sensitivity and negative psychological state") recovery. These data appear to suggest that central sensitisation during the acute-phase resolves for many, but is a precursor to the transition to chronicity when combined with other psychological features. Perspective: Central sensitisation signs during early-acute low back pain does not necessarily precede poor outcome, but may be sustained in conjunction with other psychological factors and facilitate pain persistence.
Learn More >Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available.
Learn More >Regional anesthesia may mitigate the risk of persistent postoperative pain (PPP). This Cochrane review, published originally in 2012, was updated in 2017.
Learn More >Sensory neurons exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The aim of this study is to elucidate mechanisms underlying sex-dependent PRL sensitivity in sensory neurons. Quantitative RT-PCR show that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlr ;Rosa26 reporter mice, percentages of Prlr sensory neurons in female and male DRG are also similar. Characterization of Prlr DRG neurons using immunohistochemistry and electrophysiology revealed that Prlr DRG neurons are mainly peptidergic nociceptors in females and males. However, sensory neuron type-dependent expression of Prlr is sex dimorphic. Thus, Prlr populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr DRG neurons are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurons in females. Specifically, Prlr /IB4 /CGRP neurons are 4-5-fold higher in numbers in female DRG. In contrast, Prlr /IB4 /CGRP /5HT3a /NPYR2 are predominant in male DRG. Prlr /IB4 /CGRP , Prlr /IB4 /CGRP and Prlr /IB4 /CGRP /NPYR2 neurons are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism whereby sensory neuron type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL. This article is protected by copyright. All rights reserved.
Learn More >Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.
Learn More >Treatment with cannabidiol (CBD) or KLS-13019 (novel CBD analog), has previously been shown to prevent paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). The mechanism of action for CBD- and KLS-13019-mediated protection now has been explored with dissociated dorsal root ganglion (DRG) cultures using small interfering RNA (siRNA) to the mitochondrial Na Ca exchanger-1 (mNCX-1). Treatment with this siRNA produced a 50-55% decrease in the immunoreactive (IR) area for mNCX-1 in neuronal cell bodies and a 72-80% decrease in neuritic IR area as determined with high-content image analysis. After treatment with 100 nM KLS-13019 and siRNA, DRG cultures exhibited a 75 ± 5% decrease in protection from paclitaxel-induced toxicity; whereas siRNA studies with 10 μM CBD produced a 74 ± 3% decrease in protection. Treatment with mNCX-1 siRNA alone did not produce toxicity. The protective action of cannabidiol and KLS-13019 against paclitaxel-induced toxicity during a 5-h test period was significantly attenuated after a 4-day knockdown of mNCX-1 that was not attributable to toxicity. These data indicate that decreases in neuritic mNCX-1 corresponded closely with decreased protection after siRNA treatment. Pharmacological blockade of mNCX-1 with CGP-37157 produced complete inhibition of cannabinoid-mediated protection from paclitaxel in DRG cultures, supporting the observed siRNA effects on mechanism.
Learn More >As new migraine prevention treatments are developed, the onset of a preventive effect, how long it is maintained and whether patients initially non-responsive develop clinically meaningful responses with continued treatment can be assessed.
Learn More >We aimed to evaluate the role of caffeinated beverage intake as a potential trigger of migraine headaches on that day or on the following day.
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