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The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.
Chronic pain is a common and undertreated nonmotor symptom in Parkinson's disease (PD). Although chronic pain is improved by L-dopa in some PD patients, the underlying mechanisms remain unclear. In this study, we established PD mice by unilateral microinjection of 6-OHDA in the medial forebrain bundle to investigate the contribution of spinal cord dopamine receptors to parkinsonian pain hypersensitivity. The von Frey filament tests and thermal pain tests revealed that these PD mice displayed decreased nociceptive thresholds in both hindpaws; intrathecal injection of L-dopa or apomorphine significantly increased the mechanical and thermal nociceptive thresholds, and the analgesic effect was mimicked by ropinirole (a D2 receptor agonist), but not SKF38393 (a D1/D5 receptor agonist), and blocked by sulpiride (a D2 receptor antagonist), but not SKF83566 (a D1/D5 receptor antagonist). Whole-cell recordings in lumber spinal cord slices showed that superficial dorsal horn (SDH) neurons in PD mice exhibited hyperexcitability, including more depolarized resting membrane potentials and more action potentials evoked by depolarizing current steps, which were mitigated by ropinirole. Furthermore, ropinirole inhibited the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in SDH neurons more strongly in PD mice than in control mice. However, sulpiride caused less disinhibition of sEPSCs in PD mice than in control mice. Taken together, our data reveal that pain hypersensitivity in PD mice is associated with hyperexcitability of SDH neurons, and both events are reversed by activation of spinal D2 receptors. Therefore, spinal D2 receptors can be promising therapeutic targets for the treatment of PD pain.
Chronic postoperative pain hinders functional recovery after bone fracture and orthopedic surgery. Recently reported evidence indicates that caspase-6 is important in excitatory synaptic plasticity and pathological pain. Meanwhile, netrin-1 controls post-synaptic recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and synaptogenesis. The present work aimed to examine whether caspase-6 and netrin-1 contribute to fracture-induced postoperative allodynia. A mouse model of tibial fracture by intramedullary pinning was generated for inducing postoperative pain. Then, paw withdrawal threshold, spinal caspase-6 activity, netrin-1 secretion, AMPAR trafficking, and spine morphology were examined. Caspase-6 inhibition and netrin-1 knockdown by shRNA were performed to elucidate the pathogenetic mechanism of allodynia and its prevention. Whole-cell patch-clamp recording was carried out to assess caspase-6's function in spinal AMPAR-induced current. Tibial fractures after orthopedic operation initiated persistent postsurgical mechanical and cold allodynia, accompanied by increased spinal active caspase-6, netrin-1 release, GluA1-containing AMPAR trafficking, spine density and AMPAR-induced current in dorsal horn neurons. Caspase-6 inhibition reduced fracture-associated allodynia, netrin-1 secretion and GluA1 trafficking. Netrin-1 deficiency impaired fracture-caused allodynia, post-synaptic GluA1 recruitment and spine plasticity. The specific GluA2-lacking AMPAR antagonist NASPM also dose-dependently prevented postoperative pain. The reduction of fracture-mediated postoperative excitatory synaptic AMPAR current in the dorsal horn by caspase-6 inhibition was compromised by recombinant netrin-1. Exogenous caspase-6 induced pain hypersensitivity, reversing by netrin-1 knockdown or co-application of NASPM. Thus, spinal caspase-6 modulation of GluA1-containing AMPAR activation and spine morphology through netrin-1 secretion is important in the development of fracture-related postsurgical pain in the mouse.
We had previously shown that a "blunt blade" stimulator can mimic the non-injurious strain phase of incisional pain, but not its sustained duration. Here we tested, whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this non-invasive surrogate model of intraoperative pain. Altogether 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the "blunt blade" (0.25 x 4 mm) on normal skin (n=36) and on skin pretreated by a high concentration capsaicin patch (8%, Qutenza®; n=36). These data were compared with an experimental incision (n=40) using quantitative and qualitative pain ratings by numerical rating scale and SES Pain Perception Scale descriptors. Capsaicin-sensitization increased blade-induced pain magnitude and duration significantly (both p<0.05), but it failed to fully match the sustained duration of incisional pain. In normal skin, the SES pattern of pain qualities elicited by the blade matched incision in pain magnitude and pattern of pain descriptors. In capsaicin-treated skin, the blade acquired a significant facilitation only of the perceived heat pain component (p<0.001), but not of mechanical pain components. Thus, capsaicin morphed the descriptor pattern of the blade to become more capsaicin-like, which is probably explained best by peripheral sensitization of the TRPV1 receptor. Quantitative sensory testing (QST) in capsaicin-sensitized skin revealed hyperalgesia to heat and pressure stimuli, and loss of cold and cold pain sensitivity. These findings support our hypothesis that the blade models the early tissue-strain related mechanical pain phase of surgical incisions.
Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in the trigeminal nerve, however imaging has primarily focused on the peripheral nerve segment due to previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography (SAGIT) to study 36 TN subjects (right sided pain) and 36 sex matched controls, to examine the trigeminal nerve (CN V), pontine decussation (TPT), and thalamocortical fibers (S1). GP classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA (GFA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) metrics were evaluated for both groups, analyzing TN vs. control groups and affected vs. unaffected sides. Classifiers that performed at greater-or-equal-to 70% accuracy were included. GP classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 RD classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls, as well as abnormalities between affected and unaffected sides.
Studies have suggested that quantitative sensory testing (QST) might hold a predictive value for development of chronic postoperative pain and the response to pharmacological interventions.This review systematically summarizes the current evidence on the predictive value of QST for chronic postoperative pain and the effect of pharmacological interventions. The main outcome measures were posttreatment pain intensity, pain relief, presence of moderate-to-severe postoperative pain, responders of 30% and 50% pain relief or validated questionnaires of pain and disability.A systematic search of MEDLINE and EMBASE yielded 25 studies on surgical interventions and 11 on pharmacological interventions. Seventeen surgical and 11 pharmacological studies reported an association between preoperative or pre-treatment QST and chronic postoperative pain or analgesic effect. The most commonly assessed QST modalities were pressure stimuli (17 studies), temporal summation of pain (TSP, 14 studies) and conditioned pain modulation (CPM, 16 studies). Of those, the dynamic QST parameters TSP (50%) and CPM (44%) were most frequently associated with chronic postoperative pain and analgesic effects. A large heterogeneity in methods for assessing TSP (n=4) and CPM (n=7) was found. Overall, most studies demonstrated low-to-moderate levels of risk of bias in study design, attrition, prognostic factors, outcome, and statistical analyses.This systematic review demonstrates that TSP and CPM show the most consistent predictive values for chronic postoperative pain and analgesic effect, but the heterogeneous methodologies reduce the generalizability and hence call for methodological guidelines.
The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery, hence vasoreactivity in the intradural arteries during migraine is unknown.Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 tesla MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined.Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (p=0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4 to 5.7 %]. Middle cerebral artery dilated by 9.4 % [95% CI: 7.1 to 11.7 %] and superficial temporal artery by 2.3 % [95% CI: 0.2 to 4.4 %].Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.
Youth with chronic pain and their parents face uncertainty regarding their diagnosis, treatment, and prognosis. Given the uncertain nature of chronic pain, and high comorbidity of anxiety among youth, intolerance of uncertainty (IU) may be critical to the experience of pediatric chronic pain. This study longitudinally examined major tenets of the Interpersonal Fear Avoidance Model of Pain, and included parent and youth IU as key factors in the model. Participants included 152 youth with chronic pain (Mage=14.23 years; 72% female) and their parents (93% female). At baseline, parents and youth reported on their IU and catastrophic thinking about youth pain; youth reported on their fear of pain, pain intensity, and pain interference; and parents reported on their protective responses to child pain. Youth reported on their pain interference three months later. Cross-lagged panel models, controlling for baseline pain interference, showed that greater parent IU predicted greater parent pain catastrophizing which, in turn, predicted greater parent protectiveness, greater youth fear of pain, and subsequently greater youth 3-month pain interference. Youth IU had a significant indirect effect on 3-month pain interference via youth pain catastrophizing and fear of pain. The results suggest that parent and youth IU contribute to increases in youth pain interference over time via increased pain catastrophizing, parent protectiveness, and youth fear of pain. Thus, parent and youth IU play important roles as risk factors in the maintenance of pediatric chronic pain over time and may be important targets for intervention.
Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain.We adopted western boltting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague Dawley rats.Levels of the Notch intracellular domain (NICD) were increased in ACC on day 7 after chronic constriction injury (CCI) surgery or spared nerve injury (SNI). Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased while the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA (shRNA)-Notch reduced NICD expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perception were also alleviated in rats subjected to CCI or SNI. This process was mainly mediated by the downstream effector Hes1, but not Hes5.Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.
Few studies all based on classical surveys have provided prevalence estimates of chronic pain (CP) in opioid-maintained patients (OMPs) but often had a limited patient sample size and a great variability in the prevalence estimates. This study sought to assess the prevalence of CP in the exhaustive population of OMPs using the capture-recapture method applied to the French nationwide healthcare database. Capture-recapture methods are increasingly used to estimate the prevalence of chronic conditions but have never been used in the specific context of CP in OMPs. Three large medical-administrative sources were used: the prescription drug database (A-list), the national hospital discharge database (M-list), and the pain center database (C-list). Between 2015-2016, 160,429 OMPs ≥15 years old were identified and age- and sex-matched with 160,429 non-OMPs. All patients treated with analgesic drugs for ≥6months (A-list) or diagnosed with CP (M and C-list) were included. Capture-recapture analyses were performed to yield CP estimates with their 95% confidence intervals [95% CI] using log-linear models. In 2015-2016, 12,765 OMPs and 2,938 non-OMPs with CP were captured. Most patients were male (67%) in OMPs and non-OMPs; median ages for OMPs and non-OMPs were 46 (interquartile range: 38-51) and 48 (41-53) years, respectively. The CP prevalence estimated in OMPs and non-OMPs ranged from 23.6% [14.9-46.2] to 32.1% [28.6-36.3] and from 7.28% [3.98-18.4] to 9.32% [7.42-12.1], respectively. This first study on CP in the exhaustive population of OMPs using the capture-recapture method demonstrated a high prevalence of CP in OMPs, three to four-fold than in the general population.