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Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

Background Fibromyalgia (FM), involving somatic, cognitive, and affective domains is often regarded as a hallmark central sensitization syndrome. Despite limited current therapeutic options, emerging understanding of its neural underpinnings offers the potential of applying novel neuromodulation strategies. Specifically, limbic dysregulation underlying abnormalities in pain modulation and somatic-affective processing, has been shown to play a key role in FM. Here, we assessed the long-term efficacy of targeted limbic self-neuromodulation for improving clinical disease burden in FM. Methods Forty-seven patients with FM participated in a double-blind, randomized, dual-control study employing a novel specialized neurofeedback probe representing amygdala activity. Patients underwent 10 sessions of either genuine neurofeedback training (NFT = 21), or sham neurofeedback training (NFS = 13), or treatment as usual (TAU = 13). Disease severity and symptom burden were assessed using the Symptom Severity Score (SSS), along with other questionnaires administered before and after treatment. A clinical follow-up was performed 10–12 months post-intervention. Results NFT led to a significant immediate and long-term reduction in the SSS (F (2,40)  = 7.32, p  = 0.00, ηp2 = 0.27) and the Fibromyalgia Impact Questionnaire (FIQ) (F (2,40)  = 9.85, p  = 0.00, ηp2 = 0.33), alongside multidomain short- and long-term clinical benefits. NFS resulted in a long-term reduction in pain but did not affect other disease measures or overall disease burden. The TAU group showed no clinical improvements. Conclusions Our findings support the intimate involvement of limbic brain areas in the pathophysiology of FM and suggest that targeted neuromodulation offers a novel, mechanism-based approach for managing multidomain symptoms in FM. Trial registration This study was preregistered with the National Institutes of Health (NIH). Registration number: NCT02146495. Name of trial registry: Targeted Limbic Self-modulation as a Potential Treatment for Patients Suffering From Fibromyalgia  https://clinicaltrials.gov/study/NCT02146495 .

Conditioned pain-related fear may contribute to hyperalgesia and central sensitization, but this has not been tested for interoceptive, visceral pain. The underlying ability to accurately predict pain is based on predictive cue properties and may alter the sensory processing and cognitive–emotional modulation of pain thus exacerbating the subjective pain experience. In this functional magnetic resonance imaging study using painful rectal distensions as unconditioned stimuli (US), we addressed changes in the neural processing of pain during the acquisition of pain-related fear and subsequently tested if conditioned stimuli (CS) contribute to hyperalgesia and increased neural responses in pain-encoding regions. N=49 healthy volunteers were assigned to one of two groups and underwent 3T fMRI during acquisition of either differential fear conditioning (predictable) or non-contingent presentation of CS and US (unpredictable). During a subsequent test phase, pain stimuli signaled randomly by the CSs were delivered. For the acquisition, results confirmed differential conditioning in the predictable but not the unpredictable group. With regard to activation in response to painful stimuli, the unpredictable compared to the predictable group revealed greater activation in pain-encoding (somatosensory cortex, insula) and pain-modulatory (prefrontal and cingulate cortices, periaqueductal grey, parahippocampus) regions. In the test phase, no evidence of hyperalgesia or central sensitization was found, but the predictable group demonstrated enhanced caudate nucleus activation in response to CS−-signaled pain. These findings support that during fear conditioning, the ability to predict pain affects neural processing of visceral pain and alters the associative learning processes underlying the acquisition of predictive properties of cues signaling pain, but conditioned pain-related fear does not result in visceral hyperalgesia or central sensitization. •We addressed the impact of fear on visceral hyperalgesia and central sensitization.•Pain-related fear was assessed through two groups of different predictability.•Pain predictability affected neural pain processes and altered associative learning.•During aversive learning, unpredictability amplified pain encoding, and modulation.•Pain-related fear does not promote visceral hyperalgesia or central sensitization.

Abstract Objective Central sensitization (CS) with low peripheral pain thresholds (PPTs) is a common finding among patients with chronic pain after whiplash (CPWI). While it has been proposed that myofascial myofascial trigger points (MTrPs) may act as modulators of central sensitization, previously reported findings are conflicting and inconclusive. The present study was designed to investigate immediate responsiveness of CS to alterations in nociceptive input. Design Controlled, double-blind, cross-over. Subjects Thirty-one patients with chronic pain (trapezius myalgia) and CS after whiplash. Methods Participants were referred by randomization to group A for injection of a single peripheral pain generator (MTrP or other discrete tender point) with local anesthetic or to group B for sham injection and cross-over. Documentation of PPT (Algometer), maximum jaw opening (caliper), and grip strength (Vigorimeter), as well as subjective overall pain (visual analog scale [VAS]), was made before and after each intervention. Results Statistical analysis of data (Student’s t test, analysis of variance) confirmed that peripheral pain thresholds were significantly higher and maximum jaw opening significantly greater after anesthetizing a focal pain generator in the trapezius, but not after a sham injection. In contrast with the objective variables, subjective generalized pain improved (VAS) after not only an injection of local anesthetic, but also, and to a similar extent, after a sham injection. Conclusions CS, as expressed by lowered PPT, is a rapidly adjusting physiological response to nociceptive stimuli in some patients with chronic pain after whiplash. PPT are likely modulated by myofascial tender points in selected patients with CS. With reference to the present findings, surgical ablation of MTrPs is discussed as a potential treatment modality for CS.

Abstract Objective Pain is common among women with gynecologic cancer and contributes to depressed mood, sleep disturbances, and likelihood of future chronic pain. Little is known about how psychosocial factors are associated with central sensitization of pain in gynecologic cancer. This study examined relations among depressive symptoms, sleep, subjective pain, and aftersensation pain (a proxy for central sensitization of pain) in gynecologic cancer. Methods Participants were 42 women (mean age [SD] = 59.60 [10.11] years) enrolled in a randomized clinical trial examining psychological intervention effects on sleep, pain, mood, and stress hormones/cytokines in gynecologic cancer. Six to eight weeks after surgery, participants completed an assessment of depressive symptoms, sleep, and subjective pain and a temporal summation of pain protocol via quantitative sensory testing (QST). Results Controlling for recent chemotherapy, history of chronic pain, and analgesic medication use, regression analyses revealed that longer sleep onset latency (SOL; B = 3.112, P = 0.039, bias-corrected and accelerated (BCa) 95% confidence interval [CI] = 0.371 to 6.014) and greater sensory pain (B = 0.695, P = 0.023, BCa 95% CI = 0.085 to 1.210) were associated with greater aftersensation pain at 15 seconds. Greater sensory pain scores were associated with greater aftersensation pain at 30 seconds (B = 0.286, P = 0.045, BCa 95% CI = 0.008 to 0.513). Depression was not associated with aftersensation pain. The overall models accounted for 44.5% and 40.4% of the variance in aftersensation pain at 15 and 30 seconds, respectively. Conclusions. Longer SOL and higher subjective sensory pain were related to greater aftersensation of experimentally induced pain in women postsurgery for gynecologic cancers. Interventions that improve sleep and subjective sensory pain during the perisurgical period may reduce risk for central sensitization of pain.

Purpose This study aimed to investigate the hypothesis that a repeated bout of eccentric exercise (ECC2) would result in smaller increase in the sensitivity of spinal nociceptive system, and smaller decrease in the local muscle blood oxygenation response in both the ipsilateral and the contralateral tibialis anterior muscle (TA) when compared with the initial bout (ECC1). It was hypothesized that the magnitude of the repeated bout effect (RBE) would be greater for the ipsilateral side than the contralateral side. Methods Twenty-six healthy young men performed two bouts of high-intensity eccentric exercise of TA separated by 2 weeks. Half of the participants used the same leg for both bouts (IPSI) and the other half used the contralateral leg for ECC2 (CONTRA). Nociceptive withdrawal reflex threshold (NWRT) and local muscle blood oxygenation were assessed for the exercised TA muscle before, immediately after, and one day after exercise. Results Significant decreases in NWRT and muscle oxygenation were observed after ECC1 ( p  < 0.05), but NWRT did not change after ECC2 in both groups. Smaller decreases in muscle oxygenation were observed after ECC2 than ECC1 in both groups with a similar magnitude of the difference between bouts, but an increase in muscle oxygen re-perfusion before ECC2 was only observed in the IPSI group. Conclusion These results suggest that contralateral RBE was associated with spinal facilitation of the neuronal pathways situated at a homologous innervation level, and it is unlikely that oxygen re-perfusion improvement plays a major role in the contralateral RBE.

Quantitative sensory testing is widely used in human research to investigate the state of the peripheral and central nervous system contributions in pain processing. It is a valuable tool to help identify central sensitization and may be important in the treatment of low back pain. The aim of this study was to evaluate changes in local and segmental hypersensitivity and endogenous pain inhibition in people with chronic nonspecific low back pain. Thirty patients with chronic low back pain and thirty healthy subjects were studied. Pressure pain thresholds (PPTs) were measured from the lumbar region and over the tibialis anterior muscle (TA). A cold pressor test was used to assess the activation of conditioned pain modulation (CPM), and PPTs in the lumbar region were recorded 30 s after immersion of participant’s foot in a bucket with cold water. People with chronic low back pain have significantly lower PPT than controls at both the lumbar region [89.5 kPa (mean difference) 95 % CI 40.9–131.1 kPa] and TA [59.45 kPa (mean difference) 95 % CI 13.49–105.42 kPa]. During CPM, people with chronic low back pain have significantly lower PPT than controls in lumbar region [118.6 kPa (mean difference) 95 % CI 77.9–159.2 kPa]. Women had significantly lower PPTs than men in both lumbar region [101.7 kPa (mean difference) 95 % CI 37.9–165.7 kPa] and over the TA [189.7 kPa (mean difference) 95 % CI 14.2–145.2 kPa]. There was no significant difference in PPTs in men between healthy controls and those with low back pain, suggesting the significant differences are mediated primarily by difference between women.

Background Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM. Methods An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1β protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1β antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1β in the TNC was evaluated by immunofluorescence staining. Results Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1β. Blockade of NLRP3 or IL-1β reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1β were mainly expressed in microglia in the TNC, and the IL-1β receptor, IL-1R, was mainly expressed in neurons in the TNC. Conclusions These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM.

Background Postherpetic neuralgia (PHN) is a classic chronic condition with multiple signs of peripheral and central neuropathy. Unfortunately, the pathogenesis of PHN is not well defined, limiting clinical treatment and disease management. Objective To describe the peripheral and central pathological axes of PHN, including peripheral nerve injury, inflammation induction, central nervous system sensitization, and brain functional and structural network activity. Methods A bibliographic survey was carried out, selecting relevant articles that evaluated the characterization of the pathogenesis of PHN, including peripheral and central pathological axes. Results Currently, due to the complexity of the pathophysiological mechanisms of PHN and the incomplete understanding of the exact mechanism of neuralgia. Conclusion It is essential to conduct in‐depth research to clarify the origins of PHN pathogenesis and explore effective and comprehensive therapies for PHN.

Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC)/and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP. •Mesocortical and mesolimbic connectivity decreased in cLBP patients compared to controls.•Mesocortical and mesolimbic connectivity increased when back pain intensity increased.•Mesolimbic connectivity mediated the association between pain sensitivity and cLBP severity.