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The complex neuroimmunological interactions mediated by chemokines are suggested to be responsible for the development of neuropathic pain. The lack of knowledge regarding the detailed pathomechanism of neuropathy is one reason for the lack of optimally efficient therapies. Recently, several lines of evidence indicated that expression of CCR2 is increased in spinal cord neurons and microglial cells after peripheral nerve injury. It was previously shown that administration of CCR2 antagonists induces analgesic effects; however, the role of CCR2 ligands in neuropathic pain still needs to be explained. Thus, the goal of our studies was to investigate the roles of CCL2, CCL7, and CCL12 in neuropathic pain development and opioid effectiveness. The experiments were conducted on primary glial cell cultures and two groups of mice: naive and neuropathic. We used chronic constriction injury (CCI) of the sciatic nerve as a neuropathic pain model. Mice intrathecally received chemokines (CCL2, CCL7, CCL12) at a dose of 10, 100 or 500 ng, neutralizing antibodies (anti-CCL2, anti-CCL7) at a dose of 1, 4 or 8 μg, and opioids (morphine, buprenorphine) at a dose of 1 μg. The pain-related behaviors were assessed using the von Frey and cold plate tests. The biochemical analysis of mRNA expression of glial markers, CCL2, CCL7 and CCL12 was performed using quantitative reverse transcriptase real-time PCR. We demonstrated that CCI of the sciatic nerve elevated spinal expression of CCL2, CCL7 and CCL12 in mice, in parallel with microglia and astroglial activation markers. Moreover, intrathecal injection of CCL2 and CCL7 induced pain-related behavior in naive mice in a dose-dependent manner. Surprisingly, intrathecal injection of CCL12 did not influence nociceptive transmission in naive or neuropathic mice. Additionally, we showed for the first time that intrathecal injection of CCL2 and CCL7 neutralizing antibodies not only attenuated CCI-induced pain-related behaviors in mice but also augmented the analgesia induced by morphine and buprenorphine. In vitro studies suggest that both microglia and astrocytes are an important cellular sources of the examined chemokines. Our results revealed the crucial roles of CCL2 and CCL7, but not CCL12, in neuropathic pain development and indicated that pharmacological modulation of these factors may serve as a potential therapeutic target for new (co)analgesics.
Learn More >The relationship between high sensitivity C-reactive protein and migraine is unclear. The aim of this cross-sectional population-based study was to investigate the association between high sensitivity C-reactive protein and types of headache, and to evaluate the impact of insomnia on this association.
Learn More >Previous studies have shown a robust correlation between variability of clinical pain scores and responsiveness to placebo (but not active drug) in pain studies, but explanations for these relationships are lacking. We investigated this further by assessing relationship between the Focused Analgesia Selection Test (FAST); a psychophysical method that quantifies pain reporting variability in response to experimental stimuli, variability of daily clinical pain scores as captured via diary, and response to treatment in the context of a randomized controlled crossover trial of naproxen vs. placebo in knee osteoarthritis. Evoked pain using the Staircase-Evoked Pain Procedure (StEPP®) served as the primary efficacy endpoint. Variability of daily pain scores and the FAST were assessed at baseline. Fifty-five subjects completed the study and were included in the analyses. Our results indicated a statistically significant, moderate linear relationship between variability of clinical and experimental pain reports (r= -0.416, P=0.004); and both also correlated with the placebo response (r= 0.393, P=0.004; r=-0.371, P=0.009 respectively), but only the FAST predicted the treatment difference between naproxen and placebo, as demonstrated both in a regression model (P=0.002, Beta=0.456, t=3.342) and in a Receiver Operator Curve analysis (ROC=0.721). Our results extend previous findings to include a correlation between experimental pain variability and the placebo response, and suggest that experimental pain variability is a better predictor of patients who respond preferentially to drug over placebo. A theoretical model unifying these observations is proposed and practical implications are discussed.
Learn More >This systematic review summarises evidence assessing endogenous pain inhibition in people with irritable bowel syndrome (IBS) compared with healthy controls using conditioned pain modulation (CPM) and offset analgesia (OA). Evidence regarding the role of psychological variables is also examined. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four electronic databases were searched to retrieve studies assessing CPM or OA in adults diagnosed with IBS according to the ROME II/III criteria. Standardized mean differences were calculated for each study and a random effects model was used for meta-analysis. Eleven studies were included, 5 of which reported results on the relationship between CPM and psychological variables. None of the studies assessed OA. The risk of bias assessment found a lack of assessor blinding in all studies. The pooled effect estimate was 0.90 (95% CI, 0.40-1.40) indicating a significantly lower CPM effect in people with IBS compared with controls. This effect was reduced to 0.51 when 1 outlier was excluded from the analysis. In addition, reduced CPM responses were significantly correlated with higher anxiety (r=0.17 to 0.64), stress (r=0.63), and pain catastrophizing (r=0.38) in people with IBS; however, the evidence available was limited and the strength of these associations variable. Depression was not found to be associated with CPM in these IBS cohorts. The results of this review suggest that people with IBS, as a group, demonstrate reduced pain inhibition measured by CPM. The preliminary evidence about the association between psychological factors and CPM warrants further investigations.
Learn More >When patients first develop a painful temporomandibular disorder (TMD) and seek care, 1 priority for clinicians is to assess prognosis. The authors aimed to develop a predictive model by using biopsychosocial measures from the Diagnostic Criteria for Temporomandibular Disorders (DC-TMD) to predict risk of developing TMD symptom persistence.
Learn More >Efficacy of galcanezumab in chronic migraine has been demonstrated in a pivotal Phase 3 study. Here, we assess efficacy in patients who have failed ≥2 and ≥1 prior migraine preventives for efficacy and/or safety reasons, and in those who never failed.
Learn More >Consistency of response across multiple attacks is typically measured as the proportion of study participants who achieve a categorical endpoint over a specified number of attacks (ie, 2-hour pain-free response in 2 of 3 attacks). We applied a novel analytic approach for measuring consistency of response in the acute treatment of episodic migraine using data from the COMPASS study.
Learn More >Bone cancer pain (BCP) profoundly compromises the life quality of patients with bone metastases. Severe side effects of the drugs which were widely used and effective in the various stages of this condition results in a huge challenge for BCP treatment. Here, we investigated the antinociceptive effects of XPro1595, a soluble tumor necrosis factor (solTNF) inhibitor with considerable immunoregulatory efficacy, on BCP, as well as the underlying mechanisms within the spinal dorsal horn (SDH). Walker 256 mammary gland carcinoma cells were intratibially inoculated to induce BCP. Intrathecal administration of XPro1595 alleviated bone cancer-induced chronic pain in a dose-dependent manner, with an ED of 9.69 mg/kg. Bone cancer resulted in the activation of astrocytes and microglia in the SDH through the upregulation of mitogen-activated protein kinase (MAPK) pathways, which was accompanied by an over-expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. XPro1595suppressed bone cancer-evoked glial activation and the consequent neuroinflammation. These inhibitory effects of XPro1595 were, at least partially, mediated by a reduction in the phosphorylation of p38 MAPK in spinal glial cells. In conclusion, inhibition of spinal glia by XPro1595 may have utility in the treatment of bone cancer-induced neuroinflammation, and our results further implicate XPro1595 as a new promising therapeutic agent for BCP.
Learn More >Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.
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