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Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.
Learn More >Racial and ethnic disparities in pain management are widely documented in the United States. The 2016 Centers for Disease Control and Prevention (CDC) guidelines for opioid prescribing have generated new imperatives for using complementary and alternative medicine approaches (CAM) to manage chronic pain, including cancer pain. This review's purpose was to explore the prevalence of CAM use for cancer-related pain among racial and ethnic minorities and to organize these findings according to the CAM modalities proposed by the National Center for Complementary and Integrative Health (NCCIH).
Learn More >The specific mechanism of migraine chronification remains unclear. We previously demonstrated that synaptic plasticity was associated with migraine chronification. EphB receptors and their ligands, ephrinBs, are considered to be key molecules regulating the synaptic plasticity of the central nervous system. However, whether they can promote the chronification of migraine by regulating synaptic plasticity is unknown. Therefore, we investigated the role of ephrinB/EphB signaling in chronic migraine (CM). Male Sprague-Dawley rats were used to construct a chronic migraine model by dural infusion of an inflammatory soup for 7 days. We used qPCR, western blot, and immunofluorescence to detect the mRNA and protein levels of EphB2 and ephrinB2. The paw withdrawal latency and paw withdrawal threshold were measured after lateral ventricle treatment with EphB1-Fc (an inhibitor of EphB receptor). Changes in synaptic plasticity were explored by examining synaptic-associated proteins by western blot, dendritic spines of neurons by Golgi-Cox staining, and synaptic ultrastructure by transmission electron microscopy. We found that the expression of EphB2 and ephrinB2 was increased in CM. The administration of EphB1-Fc relieved hyperalgesia and changes in synaptic plasticity induced by CM. In addition, EphB1-Fc inhibited the upregulation of NR2B phosphorylation. These results indicate that ephrinB/EphB signaling may regulate synaptic plasticity in CM via NR2B phosphorylation, which suggests the novel idea that ephrinB/EphB signaling may be a target for the treatment of migraine chronification.
Learn More >"Ion Channels and Neuropharmacology: From the Past to the Future" is the main theme of articles in Volume 60 of the . Reviews in this volume discuss a wide spectrum of therapeutically relevant ion channels and GPCRs with a particular emphasis on structural studies that elucidate drug binding sites and mechanisms of action. The regulation of ion channels by second messengers, including Ca and cyclic AMP, and lipid mediators is also highly relevant to several of the ion channels discussed, including KCNQ channels, HCN channels, L-type Ca channels, and AMPA receptors, as well as the aquaporin channels. Molecular identification of exactly where drugs bind in the structure not only elucidates their mechanism of action but also aids future structure-based drug discovery efforts to focus on relevant pharmacophores. The ion channels discussed here are targets for multiple nervous system diseases, including epilepsy and neuropathic pain. This theme complements several previous themes, including "New Therapeutic Targets," "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development," and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology."
Learn More >Gastrointestinal (GI) pain – a form of visceral pain – is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.
Learn More >A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.
Learn More >Preclinical studies on impulsive decision-making in chronic pain conditions are sparse and often contradictory. Outbred rat populations are heterogeneous regarding trait impulsivity manifestations and therefore we hypothesized that chronic pain-related alterations depend on individual traits. To test this hypothesis, we used male Wistar-Han rats in two independent experiments. Firstly, we tested the impact of spared nerve injury (SNI) in impulsive behavior evaluated by the variable delay-to-signal test (VDS). In the second experiment, SNI impact on impulsivity was again tested, but in groups previously categorized as high (HI) and low (LI) trait impulsivity in the VDS. Results showed that in an heterogenous population SNI-related impact on motor impulsivity and delay intolerance cannot be detected. However, when baseline impulsivity was considered, HI showed a significantly higher delay intolerance than the respective controls more prevalent in left-lesioned animals and appearing to result from a response correction on prematurity from VDS I to VDS II, which was present in Sham and right-lesioned animals. In conclusion, baseline differences should be more often considered when analyzing chronic pain impact. While this study pertained to impulsive behavior, other reports indicate that this can be generalized to other behavioral dimensions and that trait differences can influence not only the manifestation of comorbid behaviors but also pain itself in a complex and not totally understood manner.
Learn More >Neuronal activity can be modulated by mechanical stimuli. To study this phenomenon quantitatively, we mechanically stimulated rat cortical neurons by shear stress and local indentation. Neurons show 2 distinct responses, classified as transient and sustained. Transient responses display fast kinetics, similar to spontaneous neuronal activity, whereas sustained responses last several minutes before returning to baseline. Local soma stimulations with micrometer-sized beads evoke transient responses at low forces of ∼220 nN and pressures of ∼5.6 kPa and sustained responses at higher forces of ∼360 nN and pressures of ∼9.2 kPa. Among the neuronal compartments, axons are highly susceptible to mechanical stimulation and predominantly show sustained responses, whereas the less susceptible dendrites predominantly respond transiently. Chemical perturbation experiments suggest that mechanically evoked responses require the influx of extracellular calcium through ion channels. We propose that subtraumatic forces/pressures applied to neurons evoke neuronal responses via nonspecific gating of ion channels.
Learn More >Codeine is one of the most common opioid medicines for treating pain. Australia introduced policy changes in February 2018 to up-schedule codeine to prescription-only medicine due to concerns of adverse effects, opioid dependency and overdose-related mortality. This study investigated the frequency and content of messages promoted on Twitter by four Australian peak pain organizations, pre- and post-policy implementation. A time series analysis examined frequency of Twitter posts over a 48-week period. Text analysis via Leximancer examined message content. Results showed that promotion and education of the pending policy change dominated the Twitter feed prior to up-scheduling. However, immediately following policy change, there was a shift in content towards promoting conferences and research, and a significant decrease in the frequency of codeine-related posts, compared to opioid-related non-codeine posts. The findings suggest that pain organizations can provide timely and educational policy dissemination in the online environment. They have implications for individuals with chronic pain who use the Internet for health information and the degree to which they can trust these sources, as well as health professionals. Further research is required to determine if public health campaigns can be targeted to prevent opioid-related harm and improve pain care via this increasingly used medium. Perspective: This study presents a first look at what information is being communicated by influential pain organizations who have an online Twitter presence and how messages were delivered during a major policy change restricting access to codeine medicines. Insights could drive targeted future online health campaigns for improved pain management.
Learn More >A major function of GPCRs is to inhibit presynaptic neurotransmitter release, requiring ligand-activated receptors to couple locally to effectors at terminals. The current understanding of how this is achieved is through receptor immobilization on the terminal surface. Here, we show that opioid peptide receptors, GPCRs that mediate highly sensitive presynaptic inhibition, are instead dynamic in axons. Opioid receptors diffuse rapidly throughout the axon surface and internalize after ligand-induced activation specifically at presynaptic terminals. We delineate a parallel regulated endocytic cycle for GPCRs operating at the presynapse, separately from the synaptic vesicle cycle, which clears activated receptors from the surface of terminals and locally reinserts them to maintain the diffusible surface pool. We propose an alternate strategy for achieving local control of presynaptic effectors that, opposite to using receptor immobilization and enforced proximity, is based on lateral mobility of receptors and leverages the inherent allostery of GPCR-effector coupling.
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