Meta-analysis of the effects of anti-migraine therapeutics in the rat trigeminovascular nociception model as a tool for design optimization.

The main reasons for the low reliability of results from preclinical studies are the lack of prior sample size calculations and poor experimental design. Here, we demonstrate how the tools of meta-analysis can be implemented to tackle these issues. We conducted a systematic search to identify controlled studies testing established migraine treatments in the electrophysiological model of trigeminovascular nociception (EMTVN). Drug effects on the two outcomes, dural stimulation-evoked responses and ongoing neuronal activity were analysed separately using a three-level model with robust variance estimation. According to the meta-analysis, which included 21 experiments in rats reported in 13 studies, these drugs significantly reduced trigeminovascular nociceptive traffic, affecting both outcomes. Based on the estimated effect sizes and outcome variance, we provide guidance on sample sizes allowing to detect such effects with sufficient power in future experiments. Considering the revealed methodological features that potentially influence the results and the main source of statistical bias of the included studies, we discuss the translational potential of the EMTVN and the steps needed to improve it. We believe that the presented approach can be used for design optimization in research with other animal models and as such deserves further validation.

The implementation of transcranial Doppler ultrasonography for preclinical study of migraine.

Transcranial Doppler ultrasonography is used to study intracranial blood flow changes associated with migraine in humans, but whether this method is helpful in preclinical settings is yet unknown. To identify changes in rat intracranial blood flow specific to trigeminovascular activation-a key process in migraine pathophysiology-we measured Doppler indices in the middle cerebral artery and basilar artery before, during, and after dural or somatosensory electrical stimulation. Hemodynamic changes specific to dural stimulation were tested further in separate experiments. After baseline recordings, the animals received cumulative infusions of valproate (100 mg/kg, trice), sumatriptan (0.3, 1, and 3 mg/kg), or saline, and dural stimulation with measurement of Doppler indices was repeated every 10 min for 1 h. Several parameters of blood flow in the rat middle cerebral artery underwent alterations specific to trigeminovascular activation. These changes, however, were insensitive to valproate and sumatriptan and diminished over time. These findings question the reliability of blood flow velocity variations in large intracranial vessels as biological markers of migraine-related processes and do not support the idea of using transcranial Doppler ultrasonography for preclinical screening of antimigraine treatments, at least in the model of acute trigeminovascular activation in rats.

Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain.

ABSTRACT: We report a systematic review and meta-analysis of studies that assessed the antinociceptive efficacy of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators on pain-associated behavioural outcomes in animal models of pathological or injury-related persistent pain. In April 2019, we systematically searched 3 online databases and used crowd science and machine learning to identify studies for inclusion. We calculated a standardised mean difference effect size for each comparison and performed a random-effects meta-analysis. We assessed the impact of study design characteristics and reporting of mitigations to reduce the risk of bias. We meta-analysed 374 studies in which 171 interventions were assessed for antinociceptive efficacy in rodent models of pathological or injury-related pain. Most experiments were conducted in male animals (86%). Antinociceptive efficacy was most frequently measured by attenuation of hypersensitivity to evoked limb withdrawal. Selective cannabinoid type 1, cannabinoid type 2, nonselective cannabinoid receptor agonists (including delta-9-tetrahydrocannabinol) and peroxisome proliferator-activated receptor-alpha agonists (predominantly palmitoylethanolamide) significantly attenuated pain-associated behaviours in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol significantly attenuated pain-associated behaviours in neuropathic pain models but yielded mixed results in inflammatory pain models. The reporting of criteria to reduce the risk of bias was low; therefore, the studies have an unclear risk of bias. The value of future studies could be enhanced by improving the reporting of methodological criteria, the clinical relevance of the models, and behavioural assessments. Notwithstanding, the evidence supports the hypothesis of cannabinoid-induced analgesia.

Differential effects of the Piezo1 agonist Yoda1 in the trigeminovascular system: An electrophysiological and intravital microscopy study in rats.

Migraine is associated with the activation and sensitisation of the trigeminovascular system and is often accompanied by mechanical hyperalgesia and allodynia. The mechanisms of mechanotransduction during a migraine attack are yet unknown. We have proposed that the ion channel Piezo1 may be involved, since it is expressed in endothelial cells as well as in trigeminal ganglion neurons, and thus, may contribute to the activation of both the vascular and neuronal component of the trigeminovascular system. We took advantage of extracellular recordings from the trigeminocervical complex - a key relay centre in the migraine pain pathway, to directly assess the impact of the differently applied Piezo1 agonist Yoda1 on the sensory processing at the spinal level. At a low dose, Yoda1 slightly facilitated the ongoing firing of central trigeminovascular neurons, however, at a high dose, this substance contributed to the suppression of their activity. Using intravital microscopy, we have revealed that Yoda1 at high dose can also induce the dilation of meningeal arteries innervated by trigeminal afferents. Collectively, here we have identified both neuronal and vascular modulation via selective activation of mechanosensitive Piezo1 channels, which provide new evidence in favour of the Piezo1 role in migraine pathogenesis. We propose several mechanisms that may underlie the revealed effects of Yoda1.

The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.

Trace amine-associated receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.

The Influence of Metoclopramide on Trigeminovascular Nociception: Possible Anti-migraine Mechanism of Action.

Metoclopramide is widely used as an abortive migraine therapy due to the advantage of having not only antiemetic, but also analgesic properties. Despite the proven clinical efficacy of metoclopramide in acute migraine, the mechanism of its anti-cephalalgic action has not been entirely elucidated. Taking into account the key role of the trigeminovascular system activation in migraine pathophysiology, we aimed to investigate metoclopramide effects on the excitability of central trigeminovascular neurons and neurogenic dural vasodilation using valid electrophysiological and neurovascular models of trigeminovascular nociception. Extracellular recordings of the activity of second-order dura-sensitive neurons were made in the trigeminocervical complex (TCC) of 16 anaesthetised rats. Cumulative metoclopramide infusion (three steps in 30 min intervals, 5 mg/kg i.v. per step, n = 8) significantly and dose-dependently suppressed both ongoing firing of the TCC neurons and their responses to dural electrical stimulation, maximally to 30%[0-49%] (median[Q1-Q3]) and 4%[0-30%] of the initial level, respectively (both p = 0.001, compared to saline (n = 8)). By contrast, the neurogenic dural vasodilation studied in a separate group of 12 rats was not significantly affected by cumulative infusion of metoclopramide (5 mg/kg i.v. per step, n = 6) compared to both baseline values and the vehicle group (n = 6) (all p > 0.05). These results provide evidence that metoclopramide is unable to affect the peripheral response to trigeminovascular activation, but it does suppress the central response, which is highly predictive of anti-migraine action. Thus, here we show the neurophysiological mechanism underlying the therapeutic efficacy of metoclopramide in migraine.

Activation of trace amine-associated receptor 1 attenuates schedule-induced polydipsia in rats.

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.

Trace Amine-Associated Receptor 1 Modulates the Locomotor and Sensitization Effects of Nicotine.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for addiction treatments because it affects dopamine transmission in the mesolimbic pathway. TAAR1 is involved in the effects of addictive drugs, such as amphetamines, cocaine and ethanol, but the impact of TAAR1 on the effects of nicotine, the psychoactive drug responsible for the development and maintenance of tobacco smoking, has not yet been studied. This study was performed to investigate the possible modulatory action of TAAR1 on the effects of nicotine on locomotor behaviors in rats and mice. Pretreatment with the TAAR1 agonist RO5263397 dose-dependently decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes, prevented the development of nicotine sensitization and blocked hypermotility in nicotine-sensitized rats at the highest tested dose (10 mg/kg). The lack of TAAR1 failed to affect the effects of nicotine on the locomotion of mutant mice. Based on the results of the present study, TAAR1 activation attenuates the locomotion-stimulating effects of nicotine on rats. These results further support the previously proposed hypothesis that TAAR1 is a promising target for the prevention and treatment of drug addiction. Further studies aimed at analyzing the effects of TAAR1 agonists on animal models of nicotine addiction are warranted.

Possible approaches to CYP2C9-guided prescription of sulfonylureas in Russia.

AIM: To evaluate a possible role of CYP2C9 genotyping for sulfonylureas (SUs) prescription in Russia. MATERIALS & METHODS: We have collected the current data on correlation between SUs pharmacodynamics and CYP2C9 polymorphisms. We have evaluated the frequency of CYP2C9 polymorphisms in Russia by reviewing the literature published from 2004 to 2015 on Russian CYP2C9. RESULTS: The genotype *1/*1, which confers risk for treatment failure, has a higher frequency (81.92%) in the non-Caucasians than that (64.92%) in the Caucasians. The Caucasians have a frequency (3.58%) of the poor metabolizers (*2/*2, *2/*3 and *3/*3) eight-times higher than that (0.44%) in the non-Caucasians, predisposing an increased risk of hypoglycemia. CONCLUSION: Considering the received data and the existed knowledge on CYP2C9 influence on SUs pharmacokinetics and pharmacodynamics, we propose a possible approach to CYP2C9-guided SUs prescription for Russians.