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It has been known for decades that classical conditioning influences pain perception. However, the precise mechanism of pain modified by conditioning remains unclear, partly because of the lack of dedicated behavioral tests. In the present study, we aimed to develop a new method to detect conditioned pain using mice that were injected with formalin as an unconditioned nociceptive stimulus into the hind paw repetitively under a neutral environment. On the test day, the mice exhibited a pain-like behavior without the application of a pain stimulus in the environment. These results demonstrate that a conditioned nociceptive response can be induced by exposure alone to the environmental context in which the pain was previously experienced. The conditioned nociceptive response was sustained for at least 2 weeks. Furthermore, the conditioned nociceptive response was reduced by fentanyl but not by ibuprofen, pregabalin or fluvoxamine. This method may be useful for studying the mechanisms of irritable chronic pain and for the development of novel therapeutic strategies.
Learn More >Chronic pain is prevalent among patients with rare diseases (RDs); however, little is understood about the integration of biopsychosocial mechanisms as they relate to the unique set of clinical features and therapeutic challenges inherent in the pain conditions of patients with RDs.
Learn More >One-third of the population in the UK and worldwide struggle with chronic pain. Entraining brain alpha activity through noninvasive visual stimulation has been shown to reduce experimental pain in healthy volunteers. Neural oscillations entrainment offers a potential noninvasive and nonpharmacological intervention for patients with chronic pain, which can be delivered in the home setting and has the potential to reduce use of medications. However, evidence supporting its use in patients with chronic pain is lacking. This study explores whether (a) alpha entrainment increase alpha power in patients and (b) whether this increase in alpha correlates with analgesia. In total, 28 patients with chronic pain sat in a comfortable position and underwent 4-min visual stimulation using customised goggles at 10 Hz (alpha) and 7 Hz (control) frequency blocks in a randomised cross-over design. 64-channel electroencephalography and 11-point numeric rating scale pain intensity and pain unpleasantness scores were recorded before and after stimulation. Electroencephalography analysis revealed frontal alpha power was significantly higher when stimulating at 10 Hz when compared to 7 Hz. There was a significant positive correlation between increased frontal alpha and reduction in pain intensity (r = 0.33; P < 0.05) and pain unpleasantness (r = 0.40; P < 0.05) in the 10 Hz block. This study provides the first proof of concept that changes in alpha power resulting from entrainment correlate with an analgesic response in patients with chronic pain. Further studies are warranted to investigate dose-response parameters and equivalence to analgesia provided by medications.
Learn More >Although chronic local inflammation in deeper tissues after skin wound healing might produce chronification of acute postsurgical pain, its mechanisms have not been fully elucidated. We hypothesized that muscle injury and severe inflammation would prolong acute postsurgical pain by its central nervous system mechanisms.
Learn More >Cannabinoid (CB) receptor agonists show robust antinociceptive effects in various pain models. However, most of the clinically potent CB1 receptor-active drugs derived from cannabis are considered concerning due to psychotomimetic side effects. Selective CB receptor ligands that do not induce CNS side effects are of clinical interest. The venoms of marine snail Conus are a natural source of various potent analgesic peptides, some of which are already FDA approved. In this study we evaluated the ability of several Conus venom extracts to interact with CB1 receptor. HEK293 cells expressing CB1 receptors were treated with venom extracts and CB1 receptor internalization was analyzed by immunofluorescence. Results showed C. textile (C. Tex) and C. miles (C. Mil) samples as the most potent. These were serially subfractionated by HPLC for subsequent analysis by internalization assays and for analgesic potency evaluated in the formalin test and after peripheral nerve injury. Intrathecal injection of C. Tex and C. Mil subfractions reduced flinching/licking behavior during the second phase of formalin test and attenuated thermal and mechanical allodynia in nerve injury model. Treatment with proteolytic enzymes reduced CB1 internalization of subfractions, indicating the peptidergic nature of CB1 active component. Further HPLC purification revealed two potent antinociceptive subfractions within C. Tex with CB1 and possible CB2 activity, with mild to no side effects in the CB tetrad assessment. CB conopeptides can be isolated from these active Conus venom-derived samples and further developed as novel analgesic agents for the treatment of chronic pain using cell based or gene therapy approaches.
Learn More >Little is known about the effectiveness of placebo interventions in patients with non-specific low back pain (LBP). This systematic review assessed the magnitude of the effects of placebo interventions as compared to no intervention in randomized controlled trials(RCTs) including patients with LBP. Embase, Medline(Ovid) and Cochrane CENTRAL databases were searched from inception to December 5th, 2019. RCTs comparing placebo intervention versus no intervention in adult patients with non-specific LBP were included. Pain intensity, physical functioning and health-related quality of life (hrQoL) measured at short-, medium- and long-term follow-up were the outcomes of this review. Twenty-one RCTs were included; one concerning acute LBP and one sub-acute LBP, while 19 studies reported on chronic LBP. In chronic LBP, placebo interventions were more effective than no intervention at short-term for pain intensity [standardized mean difference (SMD) = -0.37, 95% CI = -0.55 to -0.18, moderate quality evidence], physical functioning (SMD -0.19, 95% CI = -0.39 to 0.01, moderate quality evidence), and physical quality of life (Mean Difference = -2.71, 95% CI = -4.71 to 0.71, high quality evidence), respectively. These effects were not significant at medium-term follow-up and no data was available at long-term follow-up. These results show placebo interventions are more effective than no intervention at short-term in patients with chronic LBP. However, the magnitude of the effects is probably not clinically relevant (approximately 8 points on a 0-100 pain scale). Future research should identify effect modifiers and causal mechanisms explaining the short-term effects of placebo interventions in patients with chronic LBP. (PROSPERO Registration number CRD42019127465).
Learn More >Lamina I of the dorsal horn, together with its main output pathway, lamina I projection neurons, have long been implicated in the processing of nociceptive stimuli, as well as the development of chronic pain conditions. However, the study of lamina I projection neurons is hampered by technical challenges, including the low throughput and selection biases of traditional electrophysiological techniques. Here we report on a technique which employs anatomical labelling strategies and in vivo imaging to simultaneously study a network of lamina I projection neurons in response to electrical and natural stimuli. While we were able to confirm the nociceptive involvement of this group of cells, we also describe an unexpected preference for innocuous cooling stimuli. We were able to characterize the thermal responsiveness of these cells in detail and found cooling responses decline when exposed to stable cold temperatures maintained for more than a few seconds, as well as to encode the intensity of the end temperature, while heating responses showed an unexpected reliance on adaptation temperatures.
Learn More >Guidelines recommend self-management for most people living with persistent musculoskeletal low back pain (PMLBP) when surgery is ruled out. Conveying this message to patients can be challenging. This study examined patients' perceptions of reassuring communications from surgical spine team practitioners attempting to deliver this message in a single consultation.
Learn More >In recent years, the delivery of health services has undergone a major paradigm shift towards expanded outpatient services and widespread use of telemedicine. Post herpetic neuralgia (PHN) is a treatment recalcitrant neuropathic pain condition referring to pain persisting more than three months from the initial onset of an acute herpes zoster. QUTENZA® (capsaicin 8% patch) is a single 1-hour localized treatment for PHN and can provide several months of pain relief per application. However, patient access to capsaicin 8% patch is limited due to sensitive handling protocols that require the patch application to occur under physicians or healthcare professionals under the close supervision of a physician. Herein, we describe the first successful treatment of PHN at-home, using capsaicin 8% patch, performed under full supervision and instruction from a physician using video telehealth services.
Learn More >Pain is reported as the leading cause of disability in the common forms of inflammatory arthritis conditions. Acting as a key player in nociceptive processing, neuroinflammation, and neuron-glia communication, the chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how the CCL2/CCR2 system in the dorsal root ganglion (DRG) contributes to the peripheral inflammatory pain sensitization.
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