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To compare somatosensory function profiles and psychologic factors in patients with primary burning mouth syndrome (BMS) and healthy controls and to evaluate correlations of subjective pain ratings with somatosensory and psychologic parameters.
Learn More >Previously we reported that a group of inflammatory mediators significantly enhanced resurgent currents in dorsal root ganglion (DRG) neurons. To understand the underlying intracellular signaling mechanism, we investigated the effects of inhibition of extracellular signal-regulated kinases (ERK) and protein kinase C (PKC) on the enhancing effects of inflammatory mediators on resurgent currents in rat DRG neurons. We found that the ERK inhibitor U0126 completely prevented the enhancing effects of the inflammatory mediators on both Tetrodotoxin-sensitive (TTX-S) and Tetrodotoxin-resistant (TTX-R) resurgent currents in both small and medium DRG neurons. U0126 substantially reduced repetitive firing in small DRG neurons exposed to inflammatory mediators, consistent with prevention of resurgent current amplitude increases. The PKC inhibitor Bisindolylmaleimide I also showed attenuating effects on resurgent currents, although to a lesser extent compared to ERK inhibition. These results indicate a critical role of ERK signaling in modulating resurgent currents and membrane excitability in DRG neurons treated with inflammatory mediators. It is also suggested that targeting ERK-resurgent currents might be a useful strategy to reduce inflammatory pain.
Learn More >Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer; however, the mechanisms responsible for hyperalgesia are not well understood. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, in this study we examined the role for pro-inflammatory cytokines (PICs) of the PAG in regulating mechanical and thermal hyperalgesia evoked by bone cancer via PI3K-mTOR signals. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. Western blot analysis and ELISA were used to examine PI3K/Akt/mTOR and PIC receptors and the levels of IL-1β, IL-6 and TNF-α. Protein expression levels of p-PI3K/p-Akt/p-mTOR were amplified in the PAG of bone cancer rats; and blocking PI3K-mTOR pathways in the PAG attenuated hyperalgesia responses. In addition, IL-1β, IL-6 and TNF-α were elevated in the PAG of bone cancer rats and expression of their respective receptors (namely, IL-1R, IL-6R and TNFR subtype TNFR1) was upregulated. Inhibition of IL-1R, IL-6R and TNFR1 alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated PI3K-mTOR. Our data suggest that upregulation of PIC signal in the PAG of cancer rats amplifies PI3K-mTOR signal in this brain region and alters the descending pathways in regulating pain transmission; and this thereby contributes to the development of bone cancer-induced pain.
Learn More >Chronic pain is a pathological manifestation of neuronal plasticity supported by altered gene transcription in spinal cord neurons that results in long-lasting hypersensitivity. Recently, the concept that epigenetic regulators might be important in pathological pain has emerged, but a clear understanding of the molecular players involved in the process is still lacking. In this study we linked Dnmt3a2, a synaptic activity-regulated de novo DNA methyltransferase, to chronic inflammatory pain. We observed that Dnmt3a2 levels are increased in the spinal cord of adult mice following plantar injection of Complete Freund's Adjuvant (CFA), an in vivo model of chronic inflammatory pain. In vivo knockdown of Dnmt3a2 expression in dorsal horn neurons blunted the induction of genes triggered by CFA injection. Among the genes whose transcription was found to be influenced by Dnmt3a2 expression in the spinal cord is Ptgs2, encoding for Cox-2, a prime mediator of pain processing. Lowering the levels of Dnmt3a2 prevented the establishment of long-lasting inflammatory hypersensitivity. These results identify Dnmt3a2 as an important epigenetic regulator needed for the establishment of central sensitization. Targeting expression or function of Dnmt3a2 may be suitable for the treatment of chronic pain.
Learn More >This systematic review analyzed available literature on functional brain alterations in low back pain (LBP) measured with electroencephalography (EEG), as until now evidence thereof was unclear. Four electronic databases were systematically searched the 10 of March 2018, resulting in 12 included studies. Studies showed a risk of bias of 37.5%-75% using the Newcastle-Ottawa Scale for case-control studies. Limited evidence reported higher amplitudes of balance-related potentials and early components of somatosensory evoked potentials (SEP) to noxious stimuli, and altered feedback-related negativity and P300 potentials during decision-making in chronic LBP (CLBP). These findings suggest postural strategies requiring a higher cortical attention-demand, increased sensory-discriminative processing of noxious input, and altered decision-making in CLBP. However, further research is warranted as these inferences were based on single studies. Moderate evidence for unaltered amplitude of late-phase SEPs to noxious stimuli and auditory evoked potentials in LBP implies that the affective-emotional processing of stimuli might be unaffected in LBP. Furthermore, moderate evidence indicated disturbed habituation of somatosensory stimuli in LBP. Most studies examined non-specific or mixed CLBP populations, hence EEG-quantified brain activity in (sub)acute or recurrent LBP still needs to be explored. Perspective: This review presents an overview of the current understanding of the functional LBP brain measured with EEG. The limited evidence in current research suggests altered cortical function regarding balance control, somatosensory processing and decision making in LBP, and highlights opportunities for future EEG-research.
Learn More >Peripheral nerve injury causes changes in expression of multiple receptors and mediators that participate in pain processing. We investigated the expression of microRNAs (miRNAs) – a class of post-transcriptional regulators involved in many physiological and pathophysiological processes – and their potential role in the development or maintenance of chronic neuropathic pain following lingual nerve injury in human and rat. We profiled miRNA expression in Sprague-Dawley rat and human lingual nerve neuromas using TaqMan low-density array (TLDA) cards. Expression of miRNAs of interest was validated via specific probes and correlated with nerve injury-related behavioural change in rat (time spent drinking) and clinical pain (VAS score). Target prediction was performed using publicly available algorithms; gene enrichment and pathway analysis were conducted with MetaCore. Networks of miRNAs and putative target genes were created with Cytoscape; interaction of miRNAs and target genomes in rat and human was displayed graphically using CircosPlot. rno-miR-138 was upregulated in lingual nerve of injured rats versus sham controls. rno-miR-138 and rno-miR-667 expression correlated with behavioural change at day 3 post-injury (with negative [rno-miR-138] and positive [rno-miR-667] correlations between expression and time spent drinking). In human, hsa-miR-29a was downregulated in lingual nerve neuromas of patients with higher pain VAS scores (painful group), versus patients with lower pain VAS scores (non-painful). A statistically significant negative correlation was observed between expression of both hsa-miR-29a and hsa-miR-500a, and pain VAS score. Our results show that following lingual nerve injury there are highly significant correlations between abundance of specific miRNAs, altered behaviour and pain scores. This study provides the first demonstration of correlations between human miRNA levels and VAS scores for neuropathic pain, and suggests a potential contribution of specific miRNAs to the development of chronic pain following lingual nerve injury. Putative targets for candidate miRNAs include genes related to interleukin and chemokine receptors and potassium channels.
Learn More >Opioid analgesic misuse by patients with chronic non-cancer pain is increasing in Western countries. To determine the extent of opioid misuse by patients with chronic non-cancer pain followed at a French pain management clinic. A questionnaire on pain (severity, causes and management) and opioid misuse (based on the 11 DSM-V criteria for substance abuse disorders) was administered by a health professional to patients during a short hospitalization. During the study period (September 1, 2015 to March 31, 2016), 52 patients (73.1% women; median age = 50 years [IQR: 43-57]) responded to the questionnaire. Chronic pain was caused by fibromyalgia in 55.6% of patients, and was mainly classified as neurogenic (32.6%), nociceptive (30.4%), and psychosomatic (15.2%). At hospitalization, the median pain visual analog scale score was 7/10 [IQR: 6-8], despite the ongoing treatment. The opioid misuse evaluation suggested the presence of misuse in 76.9% of patients (≥2 DSM-V criteria) that was severe in 52% of patients (≥6 DSM-V criteria). Our data highlight the high prevalence of misuse of prescribed opioids by adults with chronic non-cancer pain. A consultation with an addiction specialist should be included in the management of such patients.
Learn More >Neck pain is common in migraine and tension type headache (TTH). This review aimed to examine the evidence for cervical musculoskeletal impairments in these headaches.
Learn More >The purpose of this article was to examine age-related changes in conditioned pain modulation (CPM) and temporal summation of pain (TS) using meta-analytic techniques. Five electronic databases were searched for studies that compared measures of CPM and TS between healthy, chronic pain-free younger, middle-aged, and older adults. Eleven studies were included in the final review for TS and 11 studies were included in the review of CPM. The results suggested a moderate magnitude of difference in TS between younger adults and middle-aged/older adults, with the older cohorts exhibiting enhanced TS of pain. Considerable variability existed in the magnitude of the effects sizes, which was likely due to the different experimental methodology used across studies (i.e., inter-stimulus interval, stimulus type, body location). In regards to CPM, the data revealed a large magnitude of difference between younger and older adults, with younger adults exhibiting more efficient pain inhibition. Differences in CPM between middle-aged and older adults were minimal. The magnitude of pain inhibition during CPM in older adults may depend on the use of concurrent vs. non-concurrent protocols. In summary, the data provided strong quantitative evidence of a general age-related decline in endogenous pain modulatory function as measured by TS and CPM. PERSPECTIVE: This review compared conditioned pain modulation and temporal summation of pain between younger, middle-aged, and older adults. These findings enhance our understanding of the decline in endogenous pain modulatory function associated with normal aging.
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