Browse by Audience
PY receptors (PYRs) are among the various receptors that play an important role in nociception. The goal of this research was to investigate possible PYR expression changes in the trigeminal ganglion (TRG) in bilateral masseter muscle (MM) hypersensitivity following unilateral MM inflammation. The impact of unilateral intramasseteric administration of PYR antagonist on bilateral MM hypersensitivity was also explored.
Learn More >Amid the ongoing U.S. opioid crisis, achieving safe and effective chronic pain management while reducing opioid-related morbidity and mortality is likely to require multi-level efforts across health systems, including the Military Health System (MHS), Department of Veterans Affairs (VA), and civilian sectors.
Learn More >Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aβ mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.
Learn More >Dihydroergotamine (DHE) is an ergot alkaloid derivative of substances produced by rye fungus. Ergotamine was first used in the field of gynecology and obstetrics, then used for migraine treatment a few years later. DHE was developed as a derivative of ergotamine. DHE, when compared to ergotamine, demonstrates greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, less dopaminergic agonism, and lower emetic potential. DHE can be delivered via several routes including intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), oral, and orally inhaled (although the latter two are not available in the USA and the last remains experimental only). DHE can be used in an outpatient basis in infusion centers, emergency departments, and urgent care centers, as well as inpatient treatment for admitted patients. There are protocols for adults as well as pediatric migraine treatment. DHE and other ergot alkaloids are considered contraindicated in pregnant women as they decrease uterine blood flow and increase uterine muscle contractility predisposing to spontaneous abortion. DHE during lactation is also not recommended as it can lead to gastrointestinal distress and weakness in infants; it can also suppress milk production. Caution should be taken before administering DHE in patients with cardiovascular risk factors. DHE is an older drug with an interesting history, yet it is still clinically useful today for patients with migraine attacks not responsive to triptans, who have a greater burden from migraine, and in refractory migraine.
Learn More >Influential theoretical accounts take the position that classical conditioning can induce placebo effects through conscious expectancies. In the current study two different conditioning procedures (hidden and open) were used to separate expectancy from conditioning in order to reveal the role of expectancy in the formation of nocebo hyperalgesia. Eighty-seven healthy females were randomly assigned to three groups (hidden conditioning, open conditioning, and control). Participants were selected according to the Fear of Pain Questionnaire scores and assigned to two subgroups: high and low level of fear of pain (trait). They received electrocutaneous pain stimuli preceded by either an orange or blue color. During the conditioning phase, one color was paired with pain stimuli of moderate intensity (control stimuli) and the other color was paired with pain stimuli of high intensity (nocebo stimuli) in both hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association, however just before the testing phase the expectancy of hyperalgesia induced in this way was withdrawn. In the control group, both colors were followed by control pain stimuli. During the testing phase all participants received a series of stimuli of the same intensity, regardless of the preceding color. Participants rated pain intensity, expectancy of pain intensity and fear (state). We found that nocebo hyperalgesia was induced by hidden rather than open conditioning. The hidden conditioning procedure did not produce conscious expectancies related to pain. Nocebo hyperalgesia was induced in participants with low and high fear of pain and there was no difference in the magnitude of the nocebo effect between both groups. Nocebo hyperalgesia was not predicted by the fear of upcoming painful stimuli.
Learn More >A recent randomized controlled study showed that 66.7% (66/99) and 37.4% (37/99) of people undergoing remote electrical neuromodulation (REN), a novel non-pharmacological migraine treatment, achieve pain relief and pain freedom, respectively, at 2 h post-treatment. The participants who completed the 6-weeks double-blind phase of this study were offered to participate in an open-label extension (OLE) with an active REN device. This study investigated the clinical use of REN, focusing on its potential in reducing the use of acute migraine medications. The parent study for this open-label extension (OLE) was a randomized, double-blind, sham-controlled study of acute treatment conducted on 296 participants enrolled at 12 sites in the USA and Israel. This study included a run-in phase, in which migraine attacks were treated with usual care, and an 8-weeks double-blind treatment phase. One hundred sixty participants continued in an 8-weeks OLE phase in which they could incorporate a REN device into their usual care. Medication use rate (percentage of participants who treated their attacks only with REN and avoided medications in all their attacks) and pain outcomes at 2 h post-treatment were compared between the OLE and the run-in phase in a within-subject design. The analyses were performed on 117 participants with episodic migraine. During the OLE, 89.7% of the participants treated their attacks only with REN and avoided medications in all their attacks compared with 15.4% in the run-in phase ( < 0.0001). The rates of pain relief and pain-free in at least 50% of the treatments at 2 h post-treatment were comparable (pain relief: 58.1% in the run-in phase and 57.3% in the OLE, = 0.999; pain-free: 23.1% in the run-in vs. 30.8% in the OLE, = 0.175). REN may reduce the use of acute migraine medications. Thus, incorporating REN into usual care may reduce the risk for medication overuse headache (MOH). Future studies should evaluate whether REN reduces the use of acute migraine medications in a population at risk for MOH.
Learn More >Migraine is a common neurological disorder characterized by recurrent headache episodes that accompany sensory-motor disturbances, such as higher sensitivity to touch and light, extremity heaviness or weakness, and speech or language disabilities. Worldwide, migraine is one of the top 10 causes of disability and hence poses a huge economic burden to society. On average, migraine occurs in 12% of population but its occurrence is sexually dimorphic, as it is two to three times more prevalent in women than in men. This female to male ratio of migraine prevalence is age- and sex hormone-dependent. Advancements in understanding migraine pathogenesis have also revealed an association with both genetics and epigenetics. The severity of migraine, in terms of its attack duration, headache intensity, frequency, and occurrence of migraine-associated symptoms, has generally been reported to be greater in women. Sex differences in migraine disability and comorbidities, such as psychiatric disorders, have also been noted in some population-based studies. However, research on sex-related differences in response to migraine treatments is relatively scarce. Although a general observation is that women consume more medication than men for migraine treatment, strategies for the use of abortive and preventive medications for migraine are generally similar in both sexes. This narrative review summarizes available findings on sexually distinct responses to abortive and prophylactic pharmacotherapy of migraine. Basic experimental data and clinical findings will be presented, and potential mechanisms underlying sex-based responses will be discussed to highlight the importance and value of sex-based treatment in migraine research and practice.
Learn More >Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABA, 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABA, 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.
Learn More >Accessibility of evidence-based behavioral health interventions is one of the main challenges in health care and effective treatment approaches are not always available for patients that would benefit from them. Digitization has dramatically changed the health care landscape. Although mHealth has shown promise in addressing issues of accessibility and reach, there is vast room for improvements. The integration of technical innovations and theory driven development is a key concern. Digital solutions developed by industry alone often lack a clear theoretical framework and the solutions are not properly evaluated to meet the standards of scientifically proven efficacy. On the other hand, mHealth interventions developed in academia may be theory driven but lack user friendliness and are commonly technically outdated by the time they are implemented in regular care, if they ever are. In an ongoing project aimed at scientific innovation, the mHealth Agile Development and Evaluation Lifecycle was used to combine strengths from both industry and academia in the development of ACTsmart – a smartphone-based Acceptance and Commitment Therapy treatment for adult chronic pain patients. The present study describes the early development of ACTsmart, in the process of moving the product from alpha testing to a clinical trial ready solution.
Learn More >Melatonin is a pleiotropic hormone synthesized and secreted mainly by the pineal gland in vertebrates. Melatonin is an endogenous regulator of circadian and seasonal rhythms. Melatonin is involved in many physiological and pathophysiological processes demonstrating antioxidant, antineoplastic, anti-inflammatory, and immunomodulatory properties. Accumulating evidence has revealed that melatonin plays an important role in pain modulation through multiple mechanisms. In this review, we examine recent evidence for melatonin on pain regulation in various animal models and patients with pain syndromes, and the potential cellular mechanisms.
Learn More >