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Peripheral myelin protein (PMP22) is an integral membrane protein that traffics inefficiently even in wild-type (WT) form, with only 20% of the WT protein reaching its final plasma membrane destination in myelinating Schwann cells. Misfolding of PMP22 has been identified as a key factor in multiple peripheral neuropathies, including Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome. While biophysical analyses of disease-associated PMP22 mutants show altered protein stabilities, leading to reduced surface trafficking and loss of PMP22 function, it remains unclear how destabilization of PMP22 mutations causes mistrafficking. Here, native ion mobility-mass spectrometry (IM-MS) is used to compare the gas phase stabilities and abundances for an array of mutant PM22 complexes. We find key differences in the PMP22 mutant stabilities and propensities to form homodimeric complexes. Of particular note, we observe that severely destabilized forms of PMP22 exhibit a higher propensity to dimerize than WT PMP22. Furthermore, we employ lipid raft-mimicking SCOR bicelles to study PMP22 mutants, and find that the differences in dimer abundances are amplified in this medium when compared to micelle-based data, with disease mutants exhibiting up to 4 times more dimer than WT when liberated from SCOR bicelles. We combine our findings with previous cellular data to propose that the formation of PMP22 dimers from destabilized monomers is a key element of PMP22 mistrafficking.
Learn More >Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.
Learn More >Cannabinoids are chemicals derived naturally from the cannabis plant or are synthetically manufactured. They interact directly with cannabinoid receptors or share chemical similarity with endocannabinoids (or both). Within palliative medicine, cannabinoid receptors (CB1 and CB2) may modulate some cancer symptoms: appetite, chemotherapy-induced nausea and vomiting, and mood, pain and sleep disorders. Opioid and cannabinoid receptors have overlapping neuroanatomical receptor distribution, particularly at the dorsal horn, dorsal striatum and locus coeruleus. They have a favourable safety profile compared with opioids, and cannabis-based medicines help chronic pain. While cannabidiol (CBD) has anti-inflammatory properties, tetrahydrocannabinol (THC) is the psychoactive substance for issues such as mood and sleep. Nabiximols (Sativex), a CBD:THC combination, is Food and Drug Administration approved for some multiple sclerosis symptoms and epilepsy. There has been a swift societal evolution in attitudes about use of cannabis and cannabinoid medicines for chronic pain. In the USA, 33 states have now legalised prescription-based medical cannabis for several medical conditions; Canada has had legislation since 2001 authorising medical use. The European Union (EU) recently declared all EU citizens must have access to medical cannabis over the next 4 years. The integration into medicine and routine clinical use of cannabis is fraught with information gaps, regulatory issues and scarcity of research. Each patient should have a comprehensive assessment and risk-benefit discussion before any cannabis-based intervention to avoid possible complications such as hallucinations, psychosis and potential cardiac harm.
Learn More >Low back pain (LBP) is one of the most common musculoskeletal disorders, causing significant personal and social burden. Current research is focused on the processes of the central nervous system (particularly the sensorimotor system) and body perception, with a view to developing new and more efficient ways to treat chronic low back pain (CLBP). Several clinical tests have been suggested that might have the ability to detect alterations in the sensorimotor system. These include back-photo assessment (BPA), two-point discrimination (TPD), and the movement control tests (MCT). The aim of this study was to determine whether the simple clinical tests of BPA, TPD or MCT are able to discriminate between nonspecific CLBP subjects with altered body perception and healthy controls.
Learn More >Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.
Learn More >Chronic pain is a significant co-morbidity of burn injury affecting up to 60% of survivors. Currently, no treatments are available to prevent chronic pain after burn injury. Accumulating evidence suggests that omega-3 fatty acids (O3FA) improve symptoms across a range of painful conditions. In this study, we evaluated whether low peritraumatic levels of O3FA predicts greater pain severity during the year after burn injury. Burn survivors undergoing skin autograft were recruited from three participating burn centers. Plasma O3FA (n=77) levels were assessed in the early aftermath of burn injury using liquid chromatography/mass spectrometry and pain severity was assessed via the 0-10 numeric rating scale for 1 year following burn injury. Repeated-measures linear regression analyses were used to evaluate the association between peritraumatic O3FA concentrations and pain severity during the year following burn injury. Peritraumatic O3FA concentration and chronic pain severity were inversely related; lower levels of peritraumatic O3FA predicted worse pain outcomes (β=-.002, p=.020). Future studies are needed to evaluate biological mechanisms mediating this association and to assess the ability of O3FA to prevent chronic pain following burn injury.
Learn More >Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Small and large peripheral nerve fibers can be involved in DPN. Large nerve fiber damage causes paresthesia, sensory loss, and muscle weakness, and small nerve fiber damage is associated with pain, anesthesia, foot ulcer, and autonomic symptoms. Treatments for DPN and painful DPN (pDPN) pose considerable challenges due to the lack of effective therapies. To meet these challenges, there is a major need to develop biomarkers that can reliably diagnose and monitor progression of nerve damage and, for pDPN, facilitate personalized treatment based on underlying pain mechanisms.
Learn More >Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to hidden drug administration. In a RCT we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN-DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN-DRUG+INST+COND) or infused drug without any information or sight, i.e., hidden administration (control group 1: HIDDEN-DRUG). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary endpoint: experimental itch intensity, numeric rating scale), and objective level (secondary endpoint: wheal size, mm ). Experimental-induced itch intensity decreased in all groups but at different rates (p<0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN-DRUG group (OPEN-DRUG+INST+COND: p<0.001; OPEN-DRUG+INST: p=0.009; PLAC+INST+COND: p<0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (p=0.001). Results on wheal size were similar (p=0.048), however, no significant difference between the HIDDEN-DRUG group and the PLAC+INST+COND group (p=0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice.
Learn More >Chronic pruritus is associated with a significant reduction in quality of life. Patients with chronic pruritus endorse similar levels of quality of life impairment as patients with stroke , and present with greater rates of psychiatric illnesses, such as depression and anxiety . The prevalence and clinical presentation of chronic pruritus have been suggested to vary between racial and ethnic groups..
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