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We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ receptor (K σ = 1.86 nM) and μ receptor (K μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ/μ receptor profiles, may be a potential candidate for treating neuropathic pain.
Learn More >Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity following e.g. post-operative pain after knee replacement. Other factors such as low mood, anxiety and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions, and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain patients and 29 pain-free controls, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes, and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal components analysis of CBF identified five components that significantly discriminated chronic pain patients from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default-mode, thalamus, and sensory regions. One component correlated positively to the pain sensitization score (r=.43, p=.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitisation.
Learn More >It is consistently reported that in inflammatory arthritis (IA) pain may continue despite well controlled inflammation, most likely due to interactions between joint pathology and pain pathway alterations. Nervous system alterations have been described but much remains to be understood about neuronal and central non-neuronal changes in inflammatory arthritis.Using a rat model of IA induced by intra-articular CFA injection, this study includes a thorough characterization of joint pathology, and objectives to identify peripheral innervation changes and alterations in the spinal dorsal horn (DH) that could alter DH excitatory balancing. Male and female rats displayed long-lasting pain-related behavior but, in agreement with our previous studies, other pathological alterations emerged only at later times. Cartilage vascularization, thinning and decreased proteoglycan content were not detectable in the ipsilateral cartilage until 4 weeks post-CFA. Sympathetic and peptidergic nociceptive fibers invaded the ipsilateral cartilage alongside blood vessels, complex innervation changes were observed in the surrounding skin and ipsilateral NGF protein expression was increased. In the DH, we examined innervation by peptidergic and non-peptidergic nociceptors, inhibitory terminal density, the K-Cl co-transporter KCC2, microgliosis and astrocytosis. Here, we detected the presence of microgliosis and interestingly, an apparent loss of inhibitory terminals and decreased expression of KCC2.In conclusion, we found evidence of anatomical, inflammatory and neuronal alterations in the peripheral and central nervous systems in a model of inflammatory arthritis. Together these suggest that there may be a shift in the balance between incoming and outgoing excitation, and modulatory inhibitory tone in the DH.
Learn More >The aim of the study was to compare the International Classification of Diseases, 11th revision, (ICD-11) with current terminology of vulvodynia, approved by a broad-based consensus of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS).
Learn More >The Illness Invalidation Inventory (3*I) was designed to assess individuals' perceived invalidation regarding chronic pain experiences. However, no study has yet investigated the psychometric properties of the 3*I among individuals with chronic low back pain (CLBP). Given the personal and societal impact of CLBP and the potential for invalidation associated with this condition, the current study sought to examine the psychometric properties of the 3*I among individuals with CLBP.
Learn More >Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain.
Learn More >Despite the worldwide increase in prevalence of chronic pain and the subsequent scientific interest, researchers studying the brain and brain mechanisms in pain patients have not yet clearly identified the exact underlying disease. Quantifying the neuronal interactions in electrophysiological data could help us gain insight into the complexity of chronic pain. Therefore, the aim of this study is to examine how different underlying pain states affect the processing of nociceptive information.
Learn More >Large (big)-conductance calcium-activated potassium (BK) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BK channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BK channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BK channels and ATP-sensitive potassium (K) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BK channel activation can provoke migraine in migraine patients, and whether the BK channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BK channel openers or blockers in migraine patients are needed.
Learn More >Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA.
Learn More >People with migraine have localised (i.e., cephalic) mechanical sensitivity. There is uncertainty regarding widespread (i.e., extra-cephalic) mechanical sensitivity and variations in mechanical sensitivity throughout the migraine cycle. Therefore, this study aimed (1) to comprehensively assess mechanical sensitivity in both cephalic and extra-cephalic regions during the preictal, ictal, postictal and interictal phases; and (2) to compare these findings with mechanical sensitivity at corresponding time-points and locations in healthy participants.
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