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Opioid therapy is the cornerstone of treatment for acute procedural and postoperative pain and is regularly prescribed for severe and debilitating chronic pain conditions. Although beneficial for many patients, opioid therapy may have side effects, limited efficacy, and potential negative outcomes. Multidisciplinary pain management treatments incorporating pharmacological and integrative non-pharmacological therapies have been shown to be effective in acute and chronic pain management for pediatric populations. A multidisciplinary approach can also benefit psychological functioning and quality of life, and may have the potential to reduce reliance on opioids. The aims of this paper are to: (1) provide a brief overview of a multidisciplinary pain management approach for pediatric patients with acute and chronic pain, (2) highlight the mechanisms of action and evidence base of commonly utilized integrative non-pharmacological therapies in pediatric multidisciplinary pain management, and (3) explore the opioid sparing effects of multidisciplinary treatment for pediatric pain.
Learn More >The purpose of this review is to evaluate evidence from the last 3 years on complementary and integrative medicine treatment options for episodic migraine. Using Pubmed, Embase, and Cochrane databases, research published from 2015-2018 evaluating the modalities of mind/body therapies, supplements, and manual therapies for treatment of migraine were assessed.
Learn More >In this review, we discussed the types and frequencies of trigger factors of primary headache [migraine and tension-type headache (TTH)] among adult patients. We assessed the influence of geographical location, ethnicity and gender on the various trigger factors of a migraine and a TTH. We also evaluated the trigger factors among the multi-ethnic Southeast Asian adult patients. In a recent study, odor triggered more migrainous headaches compared to the other primary headaches. Odor was observed to be specific of migraines. Moreover, stress is one of the most common trigger factors for patients with migraines and TTHs worldwide. Migrainous patients have an increased sensitivity in comparison to non-migrainous patients. Furthermore, these patients have much difficulty in adapting to the high level of sensitivity, and the sensitized brain is therefore more vulnerable to trigger factors. In addition, the presence of one trigger factor may increase the exposure of other trigger factors. This phenomenon is more marked in the patients with migraines who have stress and menstruation as triggers, predisposing them to be more sensitive to other triggers. In conclusion, the geographical location factor has an influence on the trigger factors of headaches. Ethnicity may have an effect due to the cultural differences. Change in weather and sunlight are important commonly identified trigger factors for headaches. Moreover, gender differences in some trigger factors are present among the patients with headaches, especially sunlight and sleep deprivation. More research studies can be conducted to have a better understanding on trigger factors in the future. This will enable proper identification of trigger factors, leading to a decrease in the number of headache episodes and an improvement in quality of life for patients.
Learn More >People with migraine disease face many challenges, and these challenges can be magnified when someone is part of an "underserved" population. We set out to examine various categories of "underserved" populations, consider the unique challenges faced by these groups, and discuss mechanisms to mitigate these challenges as much as possible.
Learn More >Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
Learn More >Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective control and reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons. Optogenetic activation of this circuit induces aversion. In contrast, caudal VTA (cVTA) GABAergic neurons mainly target DRN serotonergic neurons, and activation of this circuit promotes reward. Importantly, μ-opioid receptors (MOPs) are selectively expressed at rVTA→DRN GABAergic synapses, and morphine depresses the synaptic transmission. Chronically elevating the activity of the rVTA→DRN pathway specifically interrupts morphine-induced conditioned place preference. This opioid-modulated inhibitory circuit may yield insights into morphine reward and dependence pathogenesis.
Learn More >Neuropathic pain is a significant public health challenge, yet the underlying mechanisms remain poorly understood. Painful small fiber neuropathy (SFN) may be caused by gain-of-function mutations in Nav1.8, a sodium channel subtype predominantly expressed in peripheral nociceptive neurons. However, it is not clear how Nav1.8 disease mutations induce sensory neuron hyperexcitability. Here we studied two mutations in Nav1.8 associated with hypersensitive sensory neurons: G1662S reported in painful SFN and T790A which underlies increased pain behaviors in the transgenic mouse strain. We show that in male rat dorsal root ganglion (DRG) neurons these mutations, which impair inactivation, significantly increase TTX-resistant resurgent sodium currents mediated by Nav1.8. The G1662S mutation doubled resurgent currents and the T790A mutation increased them four-fold. These unusual currents are typically evoked during the repolarization phase of action potentials. We show that the T790A mutation greatly enhances DRG neuron excitability by reducing current threshold and increasing firing frequency. Interestingly, the mutation endows DRG neurons with multiple early afterdepolarizations and leads to substantial prolongation of action potential duration. In DRG neurons, siRNA knockdown of sodium channel β4 subunits fails to significantly alter T790A current density, but reduces TTX-resistant resurgent currents by 56%. Furthermore, DRG neurons expressing T790A channels exhibited reduced excitability with fewer EADs and narrower action potentials after β4 knockdown. Together our data demonstrate that open-channel block of TTX-resistant currents, enhanced by gain-of-function mutations in Nav1.8, can make major contributions to the hyperexcitability of nociceptive neurons, likely leading to altered sensory phenotypes including neuropathic pain in SFN. This work demonstrates that two disease mutations in the voltage-gated sodium channel Na1.8 that induce nociceptor hyperexcitability increase resurgent currents. Nav1.8 is crucial for pain sensations. Because resurgent currents are evoked during action potential repolarization they can be crucial regulators of action potential activity. Our data indicate that increased Nav1.8 resurgent currents in DRG neurons greatly prolong action potential duration and enhance repetitive firing. We propose that Nav1.8 open channel block is a major factor in Nav1.8 associated pain mechanisms and that targeting the molecular mechanism underlying these unique resurgent currents represents a novel therapeutic target for the treatment of aberrant pain sensations.
Learn More >A major challenge in biology is to link cellular and molecular variations with behavioral phenotypes. Here, we studied somatosensory neurons from a panel of bird species from the family Anatidae, known for their tactile-based foraging behavior. We found that tactile specialists exhibit a proportional expansion of neuronal mechanoreceptors in trigeminal ganglia. The expansion of mechanoreceptors occurs via neurons with intermediately and slowly inactivating mechanocurrent. Such neurons contain the mechanically gated Piezo2 ion channel whose expression positively correlates with the expression of factors responsible for the development and function of mechanoreceptors. Conversely, Piezo2 expression negatively correlates with expression of molecules mediating the detection of temperature and pain, suggesting that the expansion of Piezo2-containing mechanoreceptors with prolonged mechanocurrent occurs at the expense of thermoreceptors and nociceptors. Our study suggests that the trade-off between neuronal subtypes is a general mechanism of tactile specialization at the level of somatosensory system.
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