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Migraine is reportedly associated with several cardio-cerebrovascular diseases (CCDs), but some of these diseases have not received sufficient attention. We thus attempted to determine the associations of migraine with peripheral arterial disease (PAD), ischemic heart disease (IHD), atrial fibrillation/flutter (AF), ischemic stroke (IS), and hemorrhagic stroke (HS).
Learn More >The antinociceptive effects of major cannabinoids such as ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been extensively studied in rats. These studies have led to formulations of THC and CBD for human use; however, humans use different strains of Cannabis that contain several hundred different compounds. The contribution of these compounds to pain relief produced by Cannabis is unclear. ß-caryophyllene (BCP) is one compound found in the essential oils of Cannabis. Despite some early studies, the extent to which these compounds produce pain relief in assays of pain-evoked behaviors (i.e., von Frey and Hargreaves tests) and pain-depressed behaviors (i.e., home cage wheel running) is unclear. We hypothesized that BCP would inhibit mechanical allodynia and thermal hyperalgesia as well as restore depressed wheel running activity in male Sprague-Dawley rats with inflammatory pain. Three different doses of BCP (10, 30, and 100 mg/kg) or vehicle were administered to rats via an intraperitoneal injection after hindpaw inflammation induced by an intraplantar injection of Complete Freund's Adjuvant (CFA). Neither the low dose (10 mg/kg) nor the medium dose (30 mg/kg) of BCP reversed mechanical allodynia of the inflamed hindpaw after intraperitoneal injection. However, a high dose of BCP (100 mg/kg) reversed mechanical allodynia on the von Frey test; however, this dose did not reverse thermal hyperalgesia. A hindpaw injection of 0.1 mL CFA decreased wheel running activity as is consistent with a painful stimulus. However, neither 30 mg/kg BCP nor 100 mg/kg BCP restored pain-depressed wheel running in injured rats. These same doses of BCP did not affect wheel running in uninjured control rats. Therefore, a high dose BCP produces pain relief, although it only does so against mechanical allodynia. BCP does not restore normal activity. This suggests that although pain may be eliminated following BCP administration, a return to normal levels of activity may not be possible which raises questions about the utility of BCP to treat pain. Future studies of the pain-relieving effects of Cannabis constituents must include tests of many pain-related behaviors to understand dose-response relationships and their therapeutic potential.
Learn More >Chronic use of mu-opioid receptor (MOR) agonists, such as morphine, for pain management can lead to the rapid development of analgesic tolerance. In contrast, tolerance to morphine effects in the gastrointestinal tract develops at a different rate. This can limit the therapeutic utility of morphine as the undesired gastrointestinal effects can persist even in the absence of analgesia. It is unclear if the discrete rates of morphine tolerance are due to different underlying mechanisms. β-arrestin-2 is a multi-functional protein implicated in the mechanism of antinociceptive tolerance to opioids. We have recently shown that morphine tolerance in dorsal root ganglia nociceptive neurons is mediated via two distinct mechanisms that are dependent on the duration of drug exposure: a β-arrestin-2-dependent mechanism for short-term (15-18 hours) tolerance and a β-arrestin-2-independent mechanism for long-term (7 days) tolerance (Muchhala et al., 2021, European Journal of Pharmacology). In the gastrointestinal tract, myenteric plexus neurons regulate intestinal motility. However, it is not clear if morphine engages the same molecular mechanisms for tolerance development in myenteric plexus neurons and dorsal root ganglia neurons. Therefore, in the present study we investigated the role of β-arrestin-2 in the development of morphine tolerance in myenteric plexus neurons of the mouse ileum. Here, we used whole-cell patch clamp electrophysiology to examine morphine tolerance in individual ileum myenteric plexus neurons treated with 10 µM morphine for 15-18 hours or isolated from mice treated with morphine for 7 days. Acute 3 µM morphine significantly increased the threshold to fire action potentials in naïve myenteric plexus neurons. However, this effect was not observed in wild-type neurons exposed to morphine for 15 -18 hours or isolated from mice treated with morphine for 7 days, indicating the development of tolerance. Furthermore, genetic deletion of β-arrestin-2 did not prevent the development of morphine tolerance in ileum neurons. In contrast, Bisindolylmaleimide XI, a selective protein kinase C inhibitor, reversed tolerance in ileum myenteric plexus neurons exposed to morphine in vivo for 7 days. In these neurons acute 3 µM morphine significantly increased action potential threshold. Thus, unlike dorsal root ganglia neurons, morphine tolerance in myenteric plexus neurons does not utilize β-arrestin-2. These findings reveal a potential mechanism for the differences in the rates of tolerance to morphine and highlight the need to investigate tolerance mechanisms for mu-opioid analgesics in different tissues/neurons. These results also indicate that mu-opioid analgesics that preferentially signal through G-proteins over β-arrestin-2 i.e. biased agonists, such as Oliceridine, may induce tolerance in the ileum.
Learn More >For patients with chronic pain or cancer-related pain, the most common indication for sympathetic block is to control visceral pain arising from malignancies or other alterations of the abdominal and pelvic viscera. When it is recalcitrant to conservative care, or if the patient is intolerant to pharmacotherapy, consideration of sympathetic blocks or neurolytic procedures is considered. Potential advantages of a neurolytic procedure, compared with spinal and epidural anesthetic infusions, include cost savings and avoidance of hardware. Interventional therapies that target afferent visceral innervation via the sympathetic ganglia offer effective and durable analgesia and improve multiple metrics of quality of life.
Learn More >Migraine is a prevalent disorder and a cause of high disability, influenced by modifiable and non-modifiable risk factors. Comorbid and psychiatric illnesses are prevalent in migraine patients and should be considered when choosing preventive drugs. There have been unforeseen problems with the use of preventive treatment of migraine with oral drugs, mainly due to side-effects that cannot be tolerated and lack of efficacy, leading to high discontinuation rates. Anti-CGRP monoclonal antibodies (mAbs) have shown better tolerance profiles, based on the low dropout rates in clinical trials due to adverse events. First-line therapy is a term most expressed in some medical specialties that adopt standardized protocol treatments and may not be suitable for treating migraine. Regarding efficacy, mAbs don't seem to perform much better than the current prophylactic oral drugs in reduction of monthly migraine days compared to placebo. Monoclonal antibodies against CGRP pathway have been prescribed recently, which raises some concern about their safety in the long term. Only side effects observation will confirm whether CGRP blockade causes susceptibility to severe side-effects, at least to specific subpopulations. CGRP may play a role in regulating uteroplacental blood flow and myometrial and uterine relaxation, as well as blood pressure control, raising the suspicion that its blockade could cause complications during pregnancy. Recent guidelines retain the recommendation of starting preventive treatment of migraine with oral drugs. Both the fact that it is new and costs are the reason why guidelines recommend the prescription of mAbs only after failure of at least two oral drugs.
Learn More >Oxygen therapy (OT) can relieve head pain in certain primary headache disorders, including cluster headache (CH). The exact underlying mechanism is currently uncertain, but suggested mechanisms include inhibition of the trigeminoautonomic reflex, modulation of neurotransmitters, and cerebral vasoconstriction. OT is the standard for acute treatment of CH, but patients with CH often experience considerable difficulties accessing home OT due to problems with insurance coverage. Inhalation of 100% oxygen at 6-12 L/min for 15-30 min using a non-rebreather face mask is one of the most effective acute therapies for CH, but several trials have indicated the superiority of higher oxygen flow rates of up to 15 L/min and/or using a demand-valve oxygen mask that can produce very high flow rates. Two randomized controlled trials have demonstrated the efficacy of OT in migraine, but obtaining reliable evidence is considered difficult because of different inhalation protocols, varying outcome measures, and small samples. There are some reports on the efficacy of OT as an adjuvant therapy in hypnic headache, primary headache in the emergency department, and even postdural puncture headache. The goal of this review article is to expand the knowledge regarding the use of oxygen in the treatment of headache disorders.
Learn More >Diagnoses of maternal opioid use disorder (MOUD) at delivery increased more than 500% between 1999 and 2017 in the United States. Today, cases of in utero opioid exposure due to MOUD exceed cases of the most common birth defects, including cleft lip, cleft palate, clubfoot, and Down syndrome, combined. Children exposed to opioids in utero are at increased risk of adverse childhood experiences (ACEs) due to parental care being compromised by SUDs. These ACEs include abuse, neglect, loss of a parent from death or incarceration, parental divorce, and household domestic violence. Altered sensitivity to opioid analgesia later in life is one potential outcome shared by in utero opioid exposure and ACEs that may contribute to poorly controlled pain and increased risk of opioid addiction. Studies using rat models of prenatal opioid exposure (POE) or early life adversity (ELA) have shown that each decreases opioid-induced antinociception long after exposure has ceased. However, the contributions of POE and ELA, alone and in combination, to opioid analgesic response in humans remains unknown. In this study, we used a rodent model of combined POE and ELA to disambiguate their long-term effects more quickly and with greater experimental control than human studies. We hypothesized that combined POE and ELA will decrease morphine-induced antinociception in adolescence relative to POE or ELA alone. We used a two-by-two between-subjects factorial design in which timed-pregnant Long-Evans rats were exposed to morphine (15 mg/kg/day; "POE" group) or saline ("vehicle" group) via subcutaneous osmotic minipump from gestation day 9 until delivery. Litters were fostered to untreated dams then randomly assigned to normal housing or ELA conditions using a limited bedding and nesting procedure from postnatal days 3-11. Morphine-induced antinociception was measured between postnatal days 30 and 54 using a warm-water tail withdrawal (WWTW) assay. Cumulative dose-response of morphine-induced antinociception was determined on test day 0 (1.0-30 mg/kg morphine, s.c.) and test day 13 (3.0-100 mg/kg, s.c.). On test days 1-12, rats were dosed with 18 mg/kg, s.c., every 12 hours, and WWTW was conducted on odd test days. Interesting, preliminary results of this ongoing study indicate that morphine-induced antinociception was enhanced on test day 0 in POE + normal-housed males (n = 2). These rats exhibited 100% maximum possible effect (MPE) and significantly higher potency (mean ED50=5.96 mg/kg; 95% CI = -12.12, 24.05), while mean MPE for the other groups (n=2-3) was less than 70% and mean ED50>17 mg/kg. Males exhibited partial tolerance throughout the 12-day chronic morphine treatment period. In the POE + normal-housed males, MPE decreased from 100% on test day 1 to 58% on test day 11. For the remaining groups, MPE decreased from 44-57% on test day 1 to 12-23% on test day 11. Morphine was more potent in the POE + normal-housed males on test day 13 (mean ED50=66.21 mg/kg; 95% CI = -281.6, 414) than in other males (mean ED50>104.4 mg/kg). No clear group effect was observed in females. These unexpected results suggest a complex sex-dependent interaction between POE and ELA on opioid antinociception.
Learn More >Illicitly manufactured fentanyl is fueling the current overdose epidemic, and non-fentanyl mu-opioid receptor (MOR) agonists are emerging in street drug markets worldwide. The etonitazene analog, isotonitazene, is one example of a non-fentanyl MOR agonist linked to overdose deaths. Little is known about the biological effects of isotonitazene in humans or animal models. To this end, we examined the pharmacodynamics, pharmacokinetics, and metabolism of isotonitazene in rats. Male rats were fitted with surgically implanted intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. isotonitazene (3, 10, or 30 μg/kg) or its vehicle, and blood samples (0.3 mL) were collected via catheters at 15, 30, 60, 120, 240 min post-injection. Plasma was assayed for isotonitazene and its metabolites by liquid chromatography tandem mass spectrometry. Pharmacodynamic effects – including hot plate latency, catalepsy score, and body temperature – were assessed at each blood withdrawal. Isotonitazene produced dose-dependent increases in hot plate latency (ED50=4.2 μg/kg) and catalepsy (ED50=8.7 μg/kg), while 30 μg/kg produced marked hypothermia. Isotonitazene concentrations in plasma rose linearly with increasing dose, Cmax (0.5 to 6.6 ng/mL) was achieved within 15 min, and drug half-life ranged from 40 to 60 min. Isotonitazene metabolites were detectable but below the level of quantification. Analgesia, catalepsy, and hypothermia were correlated with mean isotonitazene concentrations. Radioligand binding assays revealed that N-desethyl isotonitazene displays higher affinity at MOR (Ki=2.2 nM) than the parent compound (Ki=15.8 nM). Our findings reveal that isotonitazene is a MOR agonist that is ~1000-fold more potent than morphine (ED50=4.2 mg/kg) as an analgesic agent. Plasma concentrations of isotonitazene are in the low ng/mL range, whereas metabolites are found in even lesser amounts. Although the N-desethyl metabolite of isotonitazene displays high affinity at MOR, extremely low levels are formed in vivo. The ultra-high potency of isotonitazene presents challenges for forensic detection and likely poses grave risk to users who are inadvertently exposed to the drug.
Learn More >The sympathetic nervous system (SNS) is an integral component of the body's response to stress. Once activated, the SNS has broad-reaching effects on multiple organ systems that modulate pain, behavior, and mood. Blockade of the system can improve pain associated with multiple etiologies, including vascular, visceral, and neuropathic pain. Multiple techniques are available to block the SNS and provide options that improve analgesia and can be individualized to a particular patient's needs and disease state.
Learn More >The result of more than thirty years of research, anti-CGRP monoclonal antibodies are currently the state of the art for migraine preventive therapy. Their efficacy and safety, supported by an already large and growing body of evidence, are added by many other advantages: an early onset of action, favorable posology, negligible pharmacological interaction, and a broad-reaching efficacy in many challenging clinical contexts. When compared to standard prophylactics, these novel medications seem at least as efficacious, clearly more tolerable and, consequently, with a superior adherence profile. Furthermore, recently published analyses indicate that they are cost-effective, especially among those with chronic migraine. Yet, current guidelines endorse their use only after multiple other preventives have failed or have been deemed not tolerable. Although this recommendation may have been sensible at first, the now available data strongly point that time has come for anti-CGRP monoclonal antibodies to be acknowledged as first-line treatments for migraine patients with severe disability. For these individuals, delaying treatment until several other alternatives have failed incurs in significant losses, both economically and to many relevant aspects of their lives.
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