Browse by Audience
Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood. Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore. Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.
Learn More >Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn (SDH) of the spinal cord that are involved in the modulation of nociception, the development of chronic pain and itch, and an important analgesic target for opioids. This projection is primarily inhibitory, but the relative contribution of GABAergic and glycinergic transmission is unknown and there is limited knowledge about the SDH neurons targeted. Additionally, the details of how spinal opioids mediate analgesia remain unclear, and no study has investigated the opioid modulation of this synapse. We address this using ex vivo optogenetic stimulation of RVM fibres in conjunction with whole-cell patch-clamp recordings from the SDH in spinal cord slices. We demonstrate that both GABAergic and glycinergic neurotransmission is employed and show that SDH target neurons have diverse morphological and electrical properties, consistent with both inhibitory and excitatory interneurons. Then, we describe a subtype of SDH neurons that have a glycine-dominant input, indicating that the quality of descending inhibition across cells is not uniform. Finally, we discovered that the kappa-opioid receptor agonist U69593 presynaptically suppressed most RVM-SDH synapses. By contrast, the mu-opioid receptor agonist DAMGO acted both pre- and post-synaptically at a subset of synapses, and the delta-opioid receptor agonist deltorphin II had little effect. These data provide important mechanistic information about a descending control pathway that regulates spinal circuits. This information is necessary to understand how sensory inputs are shaped and develop more reliable and effective alternatives to current opioid analgesics. Abstract figure legend We combined ex vivo optogenetic stimulation of RVM fibres with whole cell electrophysiology of SDH neurons to investigate the final synapse in a key descending pain modulatory pathway. We demonstrate that both glycine and GABA mediate signalling at the RVM-SDH synapse, that the SDH targets of RVM projections have diverse electrical and morphological characteristics, and that presynaptic inhibition is directly and consistently achieved by kappa opioid agonists. Opioid receptors shown are sized relative to the proportion of neurons that responded to its specific agonists (81 and 84percent of DF and non-DF neurons responded to kappa opioid receptor agonists, respectively. Responses that occurred in <255 percentage of neurons are not indicated here). This article is protected by copyright. All rights reserved.
Learn More >Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high-frequency and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.
Learn More >Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary.
Learn More >Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT receptor agonist, for perimenstrual attacks.
Learn More >Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.
Learn More >Chronic low back pain (LBP) shares a bidirectional relationship with sleep disturbance. Analgesics are often used for chronic LBP management however, the effects on sleep have not been thoroughly reviewed. This systematic review and meta-analysis assessed the effect of opioid and non-opioid medications on sleep in people with chronic LBP. Electronic databases were searched for randomized controlled trials which resulted in 16 eligible articles (14 studies). Sleep measures were secondary outcomes, with one study assessing sleep objectively and all other studies reporting subjective sleep. Twelve studies assessed opioid therapies whilst two studies examined non-opioid therapies. Eight studies (all opioid) were included in meta-analyses of sleep quality and sleep disturbance comparing opioid therapies with placebo-controls. Opioid therapies significantly improved sleep quality (SMD = 0.27, 95% CI: 0.17-0.36) and reduced sleep disturbance (SMD = 0.32, 95% CI: 0.25-0.40) compared to placebo-control. These findings show a clear improvement in subjective sleep associated with opioid therapies however, future studies should examine objective sleep outcomes which remain largely unexplored in chronic LBP. Addressing both pain and sleep together is important for effective management of comorbid conditions of chronic LBP and sleep disturbance due to their bidirectional relationship.
Learn More >Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain.
Neuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two F-labeled derivatives of gabapentin (trans-4-[F]fluorogabapentin and cis-4-[F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[F]fluorogabapentin having higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.
Learn More >Fibromyalgia is a complex, generalized, and diffuse chronic musculoskeletal pain. Pharmacological approaches are widely used to relieve pain and increase quality of life. Low-Dose Naltrexone (LDN) was shown to increase the nociceptive threshold in patients with fibromyalgia. Transcranial Direct Current Stimulation (tDCS) is effective for pain management.
Learn More >Patients with adolescent idiopathic scoliosis (AIS) often report chronic back pain; however, there is inadequate research on psychological factors associated with pain in this patient population. Pain catastrophizing, a psychological factor that describes a pattern of negative thoughts and feelings about pain, has been associated with poorer responses to medical treatment for pain. The purpose of this study was to report the prevalence of pain catastrophizing in the AIS population and assess its relationship with preoperative and postoperative self-reported outcomes.
Learn More >