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While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving "analgesic" therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood-brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.
Learn More >Psychological and social factors are involved in the disability and chronicity of pain. Our study aim was to investigate whether social defeat stress (SDS) as a psychophysical stress affected mechanical withdrawal thresholds in the lumbar disk herniation (LDH) rat model. Changes in microglia and astrocytes, which play important roles in neuropathic pain states, were also investigated.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
Learn More >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.
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