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Approximately 50% of individuals with fibromyalgia (a chronic widespread pain condition) have comorbid insomnia. Treatment for these comorbid cases typically target pain, but growing research supports direct interventions for insomnia (eg, cognitive behavioural treatment for insomnia (CBT-I)) in these patients. Previous research suggests sustained hyperarousal mediated by a neural central sensitisation mechanism may underlie insomnia and chronic pain symptoms in fibromyalgia. We hypothesise CBT-I will improve insomnia symptoms, improve clinical pain and reduce central sensitisation. The trial will be the first to evaluate the short-term and long-term neural mechanisms underlying insomnia and pain improvements in fibromyalgia. Knowledge obtained from this trial might allow us to develop new or modify current treatments to better target pain mechanisms, perhaps reversing chronic pain or preventing it.
Learn More >The occurrence of pain has always been closely related to a break in the balance between excitatory and inhibitory systems, and the internal relationship between these two systems has not been studied in the pathogenesis of chronic migraine (CM). In this study, we explored how inhibitory interneurons specifically modulate the glutamate-induced hyperexcitability in the periaqueductal gray (PAG) of CM rats. The CM model was established by repeated dural infusion of inflammatory soup (IS) in rats. Then, Baclofen, a gamma-aminobutyric acid type B receptor (GABABR) agonist; CGP35348, a GABABR antagonist; H89, a protein kinase A (PKA) inhibitor; and 8-Bromo-cAMP, a PKA agonist, were applied by intraventricular injection to investigate the detailed CM mechanism. Our results showed that GABABR2 mRNA and protein levels were significantly downregulated (P < .01) in the PAG of CM rats. Similarly, gamma-aminobutyric acid (GABA) and its synthetase glutamate decarboxylase 65/67 (GAD65/67) seriously decreased (P < .01), implying a deficit in the function of inhibitory interneurons in the PAG of CM rats. Afterward, the application of Baclofen and H89 alleviated the IS-evoked hyperalgesia and extenuated vesicular glutamate transporter 2 (VGLUT2), glutamate, calcitonin gene-related peptide (CGRP), and c-Fos expression by regulating the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats, while the application of CGP35348 and 8-Bromo-cAMP exactly exerted the opposite effect. Importantly, CGP35348 induced an elevation of CGRP, and VGLUT2 expression was relieved by H89. These data suggest that the loss in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through the GABABR2/PKA/SynCAM1 pathway in the PAG of CM rats.
Learn More >To evaluate secondary outcomes including changes in functioning and disability associated with galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, in patients with chronic migraine.
Learn More >Chronic headache pain is one of the most commonly reported comorbid pain conditions with post-traumatic stress disorder (PTSD) patients and resistant to effective treatment, yet no combined preclinical model of the two disorders has been reported. Here, we used a modified chronic headache pain model to investigate the contribution of single prolonged stress (SPS) model of PTSD with sodium nitroprusside (SNP)-induced hyperalgesia. Injection of SNP (2 mg/kg, i.p.) occurred every other day from day 7 to day 15 after initiation of SPS in rats. Paw withdrawal threshold (PWT) to von Frey stimuli and tail flick latencies (TFL) dramatically decreased as early as 7 days after SPS and lasted until at least day 21. Basal PWT and TFL also significantly decreased during the SNP treatment period. The lower nociceptive thresholds recovered in 6 days following the final SNP injection in SNP group, but not in SPS + SNP group. Elevated nociceptin/OFQ (N/OFQ) levels observed in cerebrospinal fluid of SPS rats were even higher in SPS + SNP group. Glial fibrillary acidic protein (GFAP) and N/OFQ peptide (NOP) receptor mRNA expression increased in dorsal root ganglia (DRG) 21 days after SPS exposure; mRNA increases in the SPS/SNP group was more pronounced than SPS or SNP alone. GFAP protein expression was upregulated in trigeminal ganglia by SPS. Our results indicate that traumatic stress exaggerated chronic SNP-induced nociceptive hypersensitivity, and that N/OFQ and activated satellite glia cells may play an important role in the interaction between both conditions.
Learn More >Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.
Learn More >Clinical tools assessing tactile acuity in people with persistent pain have limitations. Therefore, a novel and semi-automated tool was developed: The Imprint Tactile Acuity Device (iTAD).
Learn More >Neuropathic cancer pain (NcP) is associated with worse treatment responses and specific therapy indications, but a standardized clinical diagnosis of NcP is still lacking.This is a prospective observational study on cancer outpatients, comparing different clinical approaches to NcP evaluation. A three-step assessment of NcP was performed using DN4 (cut-off of 4), palliative care physician Clinical Impression, including etiology and pain syndrome identification, and Retrospective Clinical Classification by a board of specialists with the IASP Neuropathic Pain Special Interest Group criteria. NcP classification was specifically referred to pain directly due to cancer.350 patients were assessed, NcP prevalence was 20%, 95%CI [15.9% – 24.6%], 36,9%, (95% CI 31.6% – 42.1%) and 28.6%, (95%CI 23.8% – 33.9%) according respectively to DN4, Clinical Impression and Retrospective Clinical Classification. Cohen's Kappa concordance coefficient between DN4 and Retrospective Clinical Classification was 0.57, 95%CI [0.47 – 0.67], indicating moderate concordance. Higher percentages of discordance were found for specific pain syndromes like pain due to deep soft tissue infiltration and pain associated with tenesmus. Disagreement among clinicians accounted also for different NcP diagnoses and highlighted lack of homogeneous clinical criteria. Rigorous application of etiological and syndrome diagnosis to explain pain cause, associated with standardized diagnostic criteria and assessment of pain characteristics, that is also specific of the cancer pain condition could improve clinical classification of NcP.
Learn More >Approximately one-half of patients with substance use disorders (SUD) experience chronic pain. Yet how patients perceive the relationship between their substance use and chronic pain remains poorly understood. We sought to identify how patients with comorbid SUD and chronic pain describe the relationship between, and mechanisms linking, these conditions. We conducted qualitative interviews with 34 patients engaged in SUD treatment who were also diagnosed with chronic pain. Interviews were transcribed verbatim and coded by both primary and secondary coders. Qualitative content analysis guided coding and analysis. Patient interviews revealed three primary pathways. One group of participants described SUD as developing independently from their experiences of chronic pain. A second group of participants described turning to substances to self-manage or cope with the physical and emotional aspects of chronic pain. A third group of participants described encounters with opioid medications as the causal agent initiating a SUD. Our findings build upon research that has identified chronic pain and SUD as developmentally similar and mutually reinforcing, by revealing the ways in which patients themselves understand and experience the interconnections between their substance use and chronic pain.
Learn More >While clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide (AS-ODN) targeting β2-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. In contrast, glucocorticoid receptor AS-ODN, prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also a risk factor for CIPN, early life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding, NLB) and stress-resilient (produced by neonatal handling, NH) phenotypes in adults. While NLB significantly enhanced CIPN only in female adults, NH significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the two major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.
Learn More >Bone cancer pain (BCP) remains a difficult clinical problem. This study examined whether pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is effective for attenuating BCP, and investigated the interaction between activation of PPARγ and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) / mammalian target of rapamycin (mTOR) signal in the spinal dorsal horn (SDH) of BCP rats.
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