Browse by Audience
Experimental data have suggested that in neuropathic pain, tricyclic antidepressants may work solely through a β2-agonist action. The aim of this study was to test if the β2-agonist terbutaline relieves painful polyneuropathy. The study was a randomized, double-blind, placebo- and active-controlled, 3-way, cross-over trial among patients with painful polyneuropathy. The treatment periods were of 5 weeks' duration and were preceded by 1 week for washout and 1 week for baseline observations. The patients received terbutaline (5 to 15 mg), imipramine (30 to 150 mg), or placebo in random order. Drug doses depended on age and metabolizer status. Change in total pain recorded from ratings in diaries (NRS 0-10) was the primary outcome and change in rating of specific pain symptoms (NRS 0-10), patient global impression of change and sleep disturbance were secondary outcomes. Forty-seven patients were randomized. Median score for total pain changed from NRS 6.4 to 6.1 from baseline to week 5 on terbutaline with an average effect during the treatment period as compared to placebo of 0.13 (95% CI -0.12;0.38, p = 0.32). Median score for total pain on imipramine changed from NRS 6.6 to 4.8 with an average effect as compared to placebo of -1.17 (95% CI -1.42; -0.92, p < 0.001). Secondary outcomes were also unaltered by terbutaline but improved by imipramine. The β2-agonist terbutaline has no effect in painful polyneuropathy. β2 -agonism seems not to be an important mechanism of action of TCAs in neuropathic pain.
Learn More >Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms, and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Further, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a CGRP receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864) and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine, and as a screen to dissect potentially efficacious migraine therapeutic targets.
Learn More >The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries. Cholecystokinin (CCK) neurons located deeper within the dorsal horn (laminae III-IV) are important for both types of injuries. Interestingly, the Maf subset of CCK neurons is composed of transient vesicular glutamate transporter 3 (tVGLUT3) neurons, which convey primarily dynamic allodynia. Identification of an etiology-based circuitry for mechanical allodynia in the dorsal horn has important implications for the mechanistic and clinical understanding of this condition.
Learn More >The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Since reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy.
Learn More >Peripheral neuropathy is associated with enhanced activity of primary afferents which is often manifested as pain. Voltage-gated sodium channels (VGSCs) are critical for the initiation and propagation of action potentials and are thus essential for the transmission of the noxious stimuli from the periphery. Human peripheral sensory neurons express multiple VGSCs, including Nav1.7, Nav1.8, and Nav1.9 that are almost exclusively expressed in the peripheral nervous system. Distinct biophysical properties of Nav1.7, Nav1.8, and Nav1.9 underlie their differential contributions to finely tuned neuronal firing of nociceptors, and mutations in these channels have been associated with several inherited human pain disorders. Functional characterization of these mutations has provided additional insights into the role of these channels in electrogenesis in nociceptive neurons and pain sensation. Peripheral tissue damage activates an inflammatory response and triggers generation and release of inflammatory mediators, which can act through diverse signaling cascades to modulate expression and activity of ion channels including VGSCs, contributing to the development and maintenance of pathological pain conditions. In this review, we discuss signaling pathways that are activated by pro-nociceptive inflammatory mediators that regulate peripheral sodium channels, with a specific focus on direct phosphorylation of these channels by multiple protein kinases.
Learn More >Meta-analyses indicate mindfulness meditation is efficacious for chronic and acute pain, but most available studies lack active control comparisons. This raises the possibility that placebo-related processes may account, at least in part, for mindfulness effects. The objective of this study was to develop a closely matched sham mindfulness condition to establish whether placebo effects contribute to mindfulness-based interventions for pain.
Learn More >The multitude of treatments available for tens of millions of US adults with moderate/severe chronic pain have limited efficacy. Long-term opioid therapy (LTOT) is a widely available option for controlling pain among patients with chronic pain refractory to other treatments. The recent recognition of LTOT inefficacy and complications has led to more frequent opioid tapering, which in turn has revealed its own set of complications. The occurrence of the same set of symptoms-worsening pain, declining function, and clinical instability-in contrasting contexts of LTOT ineffectiveness and opioid tapering has led to increasing recognition of the utility of complex persistent opioid dependence (CPOD), a clinically distinct but biologically similar state compared with opioid use disorder as an explanatory diagnosis/heuristic. Recent guidelines for LTOT tapering have incorporated buprenorphine treatment based on CPOD concepts as a recommended treatment for problems due to opioid tapering with limited supportive evidence. The increasing utilization of buprenorphine for both LTOT ineffectiveness and opioid tapering problems raises the urgent need for a review of the clinical definition, mechanisms, and treatment of CPOD and pertinent policies. In this manuscript, we discuss various issues related to CPOD that requires further clarification through research and policy development.
Learn More >Pain in chronic pancreatitis is subdivided in a continuous or intermittent pattern, each thought to represent a different entity, requiring specific treatment. Because evidence is missing, we studied pain patterns in a prospective longitudinal nationwide study.
Learn More >Temperature-sensitive Transient Receptor Potential Vanilloid ion channel subtypes 1-4 (thermoTRPV1-4) play important roles in a wide range of physiological processes, including temperature sensing and body temperature regulation, inflammation, pain, itch, maintenance of skin, bone and hair and osmotic regulation. ThermoTRPV function is modulated by numerous natural product compounds, such as capsaicin, camphor and cannabinoids. Because of their physiological importance and their druggability, these channels have made attractive potential targets for drug development. Since the beginning of the cryo-EM "resolution revolution" a lot of progress has been made towards dissecting the activation mechanisms of thermoTRPVs and mapping the binding sites for modulatory compounds. Here we review the thermoTRPV physiology and pharmacology and summarize the current knowledge of their mechanisms of gating and ligand binding sites.
Learn More >It is known that attending to a cutaneous stimulus briefly increases its subjective intensity. The purpose of the present study was to determine whether an extended period of attention would produce a longer-lasting perceptual amplification. Eighty subjects were assigned alternately to experimental and control groups. Members of the two groups received identical series of tactile stimuli (near-threshold von Frey filaments applied to the forearm), but those in the experimental group carried out a two-interval forced-choice detection task that required attention to the filaments, while subjects in the control group attended instead to a video game. After this initial phase, all subjects gave magnitude estimates of the intensity of a wide range of von Frey filaments. The experimental group gave estimates 42% greater than those of the control group, both for filaments used in the initial phase, and others not presented previously; the perceptual amplification did not, however, transfer to a different type of pressure stimulus, a 5 mm-diameter rod applied to the skin. The aftereffect of sustained attention lasted for at least 15 min. This phenomenon, demonstrated in normal subjects, may have implications for the hypervigilance of some chronic pain patients, which is characterized by both heightened attention to pain and long-lasting perceptual amplification of noxious stimuli.
Learn More >