Browse by Audience
Excitation of dorsal root ganglion (DRG) neurons by interleukin 1β (IL-1β) is implicated in the onset of neuropathic pain. To understand its mechanism of action, isolectin B4 positive (IB) DRG neurons were exposed to 100pM IL-1β for 5-6d. A reversible increase in action potential (AP) amplitude reflected increased TTX-sensitive sodium current (TTX-S I). An irreversible increase in AP duration reflected decreased Ca- sensitive K conductance (BK(Ca) channels). Different processes thus underlie regulation of the two channel types. Since changes in AP shape facilitated Ca influx, this explains how IL-1β facilitates synaptic transmission in the dorsal horn; thereby provoking pain.
Learn More >Neuropathic pain is a common type of chronic pain caused by trauma or chemotherapy. However, this type of pain is undertreated. TsNTxP is a non-toxic protein isolated from the venom of the scorpion Tityus serrulatus, and it is structurally similar to neurotoxins that interact with voltage-gated sodium channels. However, the antinociceptive properties of this protein have not been characterized. The purpose of this study was to investigate the antinociceptive effects of TsNTxP in acute and neuropathic pain models. Male and female Swiss mice (25-30 g) were exposed to different models of acute pain (tail-flick test and nociception caused by capsaicin intraplantar injection) or neuropathic pain (chronic pain syndrome induced by paclitaxel or chronic constriction injury of the sciatic nerve). Hypersensitivity to mechanical or cold stimuli were evaluated in the models of neuropathic pain. The ability of TsNTxP to alter the release of glutamate in mouse spinal cord synaptosomes was also evaluated. The results showed that TsNTxP exerted antinociceptive effects in the tail-flick test to a thermal stimulus and in the intraplantar capsaicin administration model. Furthermore, TsNTxP was non-toxic and exerted antiallodynic effects in neuropathic pain models induced by chronic constriction injury of the sciatic nerve and administration of paclitaxel. TsNTxP reduced glutamate release from mouse spinal cord synaptosomes following stimulation with potassium chloride (KCl) or capsaicin. Thus, this T. serrulatus protein may be a promising non-toxic drug for the treatment of neuropathic pain.
Learn More >Oxaliplatin is a third-generation derivative of platinum that is effective in the treatment of multiple solid tumors. However, it can cause peripheral neuropathic pain, and the molecular mechanisms of this effect remain unknown. We induced a model of peripheral neuropathic pain in rats by intraperitoneally injecting them with oxaliplatin twice a week for 4.5 weeks. We found that both the mRNA and protein expression levels of Na1.6 (encoded by the gene Scn8a) increased while the miR-30b-5p (shorthand for miR-30b) expression decreased in the dorsal root ganglion (DRG) of treated rats. Using TargetScan and miRanda predictive software, we discovered that Scn8a was a major target of miR-30b. Moreover, we found that miR-30b negatively regulated Scn8a by binding to the Scn8a 3'UTR in PC12 cells. In addition, Na1.6 and miR-30b were colocalized in the DRG neurons of naive rats. Overexpression of miR-30b using an miR-30b agomir attenuated neuropathic pain induced by oxaliplatin and inhibited both the mRNA and protein expression levels of Na1.6 both in vitro and in vivo. Conversely, the inhibition of miR-30b with an miR-30b antagomir resulted in neuropathic pain and an increase in the expression of Na1.6. More importantly, overexpression of miR-30b inhibited the proliferation of LS-174t cells (Colorectal cancer cells). These data suggest that miR-30b contributes to oxaliplatin-induced chronic neuropathic pain through Na1.6 downregulation and could be a novel therapeutic target for the treatment of oxaliplatin-induced neuropathic pain as a side effect of chemotherapy in cancer patients.
Learn More >Chronic pain is highly prevalent among older adults where it is associated with significant suffering, disability, social isolation, and greater costs and burden to health care systems. Pharmaceutical treatment of chronic pain in older adults is usually only partially effective and is often limited by side effects including urinary retention, constipation, sedation, cognitive impairment, and increased risk of falls. Since older adults are underrepresented in clinical trials testing treatments for chronic pain, the potential impacts of polypharmacy and frailty on reported outcomes and side effect profiles are largely unknown. Thus, for current treatments providers and patients must balance anticipated benefits of pain reduction with the known and unknown risks of treatment. Chronic pain is also a risk factor for premature death as well as accelerated cognitive decline, suggesting potential shared mechanisms between persistent pain (or its treatment) and dementia. Cognitive decline and dementia may also impact pain perception and the ability to report pain, complicating treatment decisions. Associations between persistent pain and the risks of premature death and accelerated cognitive decline make estimates for chronic pain in these populations particularly challenging. Future research is needed to improve estimates for chronic pain in older adults, to elucidate underlying mechanisms of pain with aging, and to develop and advance safer, more effective treatment options for chronic pain in older adults.
Learn More >The aim of the present study was to explore the pain modulation effects of motor imagery (MI) and action observation (AO) of specific neck therapeutic exercises both locally, in the cervical region, and remotely. A single-blind, placebo clinical trial was designed. A total of 30 patients with chronic neck pain (CNP) were randomly assigned to an AO group, MI group, or placebo observation (PO) group. Pain pressure thresholds (PPTs) of C2/C3, trapezius muscles, and epicondyle were the main outcome variables. Secondary outcomes included heart rate measurement. Statistically significant differences were observed in PPTs of the cervical region in the AO and MI groups between the preintervention and first postintervention assessment. Significant differences were found in the AO group in the epicondyle between the preintervention, first and second post-intervention assessments. Regarding heart rate response, differences were found in the AO and MI groups between the preintervention and average intervention measurements. AO and MI induce immediate pain modulation in the cervical region and AO also induces remote hypoalgesia. OA appears to lead to greater pain modulation as well as a greater heart rate response, however, both should be clinically considered in patients with CNP.
Learn More >The dorsal root ganglia (DRG) contain the somas of first-order sensory neurons critical for somatosensation. Due to technical difficulties, DRG neuronal activity in awake behaving animals remains unknown. Here, we develop a method for imaging DRG at cellular and subcellular resolution over weeks in awake mice. The method involves the installation of an intervertebral fusion mount to reduce spinal movement, and the implantation of a vertebral glass window without interfering animals' motor and sensory functions. In vivo two-photon calcium imaging shows that DRG neuronal activity is higher in awake than anesthetized animals. Immediately after plantar formalin injection, DRG neuronal activity increases substantially and this activity upsurge correlates with animals' phasic pain behavior. Repeated imaging of DRG over 5 weeks after formalin injection reveals persistent neuronal hyperactivity associated with ongoing pain. The method described here provides an important means for in vivo studies of DRG functions in sensory perception and disorders.
Learn More >Mouse models of rare monogenic forms of migraine provide a unique experimental system to study the cellular and circuit mechanisms of the primary brain dysfunctions causing a migraine disorder. Here, we discuss the migraine-relevant phenotypes and the migraine-relevant functional alterations in the brain of five genetic mouse models of migraine, four of which carry mutations derived from patients with familial hemiplegic migraine (FHM) and the fifth carry a mutation from patients with both phenotypically normal MA and familial advanced sleep phase syndrome (FASPS). We focus on the latter mouse model, in which a ubiquitous serine-threonine kinase is mutated, and on two mouse models of pure FHM, in which a voltage-gated calcium channel controlling neurotransmitter release at most brain synapses and a Na/K ATPase that is expressed mainly in astrocytes in the adult brain are mutated, respectively. First, we describe the behavioral phenotypes of the genetic animal models and review the evidence that an increased susceptibility to experimentally induced cortical spreading depression (CSD) is a key migraine-relevant phenotype common to the five models. Second, we review the synaptic alterations in the cerebral cortex of the genetic models of migraine and discuss the mechanisms underlying their increased susceptibility to CSD. Third, we review the alterations in the trigeminovascular pain pathway and discuss possible implications for migraine pain mechanisms. Finally, we discuss the insights into migraine pathophysiology obtained from the genetic models of migraine, in particular regarding the mechanisms that make the brain of migraineurs susceptible to the ignition of "spontaneous" CSDs. Although the reviewed functional studies support the view of migraine as a disorder of the brain characterized by dysfunctional regulation of the excitatory/inhibitory balance in specific neuronal circuits, much work remains to be done in the genetic mouse models e.g. to identfy the relevant dysfunctional circuits and to establish whether and how the alterations in the function of specific circuits (in the cerebral cortex and/or other brain areas) are state-dependent and may, in certain conditions, favor CSD ignition and the migraine attack.
Learn More >Receptor-type ion channels are critical for detection of noxious stimuli in primary sensory neurons. Transient receptor potential (TRP) channels mediate pain sensations and promote a variety of neuronal signals that elicit secondary neural functions (such as calcitonin gene-related peptide [CGRP] secretion), which are important for physiological functions throughout the body. In this review, we focus on the involvement of TRP channels in sensing acute pain, inflammatory pain, headache, migraine, pain due to fungal infections, and osteo-inflammation. Furthermore, action potentials mediated via interactions between TRP channels and the chloride channel, anoctamin 1 (ANO1), can also generate strong pain sensations in primary sensory neurons. Thus, we also discuss mechanisms that enhance neuronal excitation and are dependent on ANO1, and consider modulation of pain sensation from the perspective of both cation and anion dynamics.
Learn More >Exergames are non-immersive versions of virtual reality that involve physical exercise and have shown several benefits on physical fitness and quality of life in women with fibromyalgia. However, the effects on brain dynamics are still unknown.
Learn More >