Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis

Personalized at-home neurofeedback compared with long-acting methylphenidate in an european non-inferiority randomized trial in children with ADHD

Neurofeedback (NF) has gained increasing interest among non-pharmacological treatments for Attention Deficit Hyperactivity Disorder (ADHD). NF training aims to enhance self-regulation of brain activities. The goal of the NEWROFEED study is to assess the efficacy of a new personalized NF training device, using two different protocols according to each child's electroencephalographic pattern, and designed for use at home. This study is a non-inferiority trial comparing NF to methylphenidate. The study is a prospective, multicentre, randomized, reference drug-controlled trial. One hundred seventy-nine children with ADHD, aged 7 to 13 years will be recruited in 13 clinical centres from 5 European countries. Subjects will be randomized to two groups: NF group (Neurofeedback Training Group) and MPH group (Methylphenidate group). Outcome measures include clinicians, parents and teachers' assessments, attention measures and quantitative EEG (qEEG). Patients undergo eight visits over a three-month period: pre-inclusion visit, inclusion visit, 4 "discovery" (NF group) or titration visits (MPH group), an intermediate and a final visit. Patients will be randomized to either the MPH or NF group. Children in the NF group will undergo either an SMR or a Theta/Beta training protocol according to their baselineTheta/Beta Ratio obtained from the qEEG. This is the first non-inferiority study between a personalized NF device and pharmacological treatment. Innovative aspects of Mensia Koala™ include the personalization of the training protocol according to initial qEEG characteristics (SMR or Theta/Beta training protocols) and an improved accessibility of NF due to the opportunity to train at home with monitoring by the clinician through a dedicated web portal. NCT02778360 . Date registration (retrospectively registered): 5-12-2016. Registered May 19, 2016

Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases

Many studies have shown the antinociceptive effects of cannabinoid (CB) agonists in different models of pain. Herein, we have investigated their relevance in neuropathic pain induced by brachial plexus avulsion (BPA) in mice.Mice underwent BPA or sham surgery. The mRNA levels and protein expression of CB(1) and CB(2) receptors were assessed by RT-PCR and immunohistochemistry, respectively. The activation of glial cells, MAP kinases and transcription factors were evaluated by immunohistochemistry. The antinociceptive properties induced by cannabinoid agonists were assessed on the 5(th) and 30(th) days after surgery. We observed a marked increase in CB(1) and CB(2) receptor mRNA and protein expression in the spinal cord and dorsal root ganglion, either at the 5(th) or 30(th) day after surgery. BPA also induced a marked activation of p38 and JNK MAP kinases (on the 30(th) day), glial cells, such as microglia and astrocytes, and the transcription factors CREB and NF-κB (at the 5(th) and 30(th) days) in the spinal cord. Systemic treatment with cannabinoid agonists reduced mechanical allodynia on both the 5(th) and 30(th) days after surgery, but the greatest results were observed by using central routes of administration, especially at the 30(th) day. Treatment with WIN 55,212-2 prevented the activation of both glial cells and MAP kinases, associated with an enhancement of CREB and NF-κB activation.Our results indicate a relevant role for cannabinoid agonists in BPA, reinforcing their potential therapeutic relevance for the management of chronic pain states

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a new therapeutic target

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioural alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioural alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioural tests. Pharmacological enhancement of GABAergic tonic-inhibition by the FDA-approved drug ganaxolone rescued functional/behavioural alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviours and identifies a new, readily-translatable therapeutic strategy for preterm brain disorders

Cannabinoid modulation of nociception and nociceptor activity during inflammation.

University of Minnesota Ph.D. dissertation. June 2009. Major: Neuroscience. Advisor: Donald Anthony Simone. 1 computer file (PDF); x, 235 pages.Previous studies have demonstrated that peripherally-administered cannabinoids at the site of injury produce antinociception in animal models of acute and persistent pain. Peripheral cannabinoid one (CB1) receptor-mediated antinociception has been attributed to CB1 receptors located on nociceptive DRG neurons and their peripheral nerve terminals. Although these studies suggest that activation of peripheral CB1 receptors located on nociceptive nerve terminals produces antinociception, how cannabinoids modulate nociceptor activity is not known. The overall aim of this thesis was to relate the behavioral antinociceptive effects of locally-administered cannabinoids with changes in the response properties of nociceptors during non-inflamed and inflamed conditions. It was hypothesized that activation of peripheral CB1 receptors attenuated nociception and nociceptor activity only during inflammation. In behavioral studies, intraplantar administration of complete Freund's adjuvant (CFA), but not saline, produced mechanical allodynia, mechanical hyperalgesia, and heat hyperalgesia. Activation of peripheral CB1 receptors produced antiallodynia and antihyperalgesia following inflammation, but did not alter nociception during non-inflamed conditions. In electrophysiological studies, only cutaneous nociceptors (Adelta and C) from inflamed skin were sensitized, and not Abeta mechanoreceptors. Local administration of CB1 receptor agonists attenuated mechanically-evoked responses of Adelta nociceptors from inflamed skin, but did not alter the evoked responses of Adelta nociceptors from non-inflamed skin. The responses of C nociceptors and Abeta mechanoreceptors from either non-inflamed or inflamed skin were not altered following local administration of cannabinoids. Our results demonstrated that peripherally-mediated cannabinoid antinociception through CB1 receptors is mediated, at least in part, by attenuation of Adelta nociceptor activity. The results from the present studies suggest that peripherally-acting CB1 receptor agonists could be administered alone or co-administered with other analgesic drugs to treat acute and persistent pain in humans and animals

Activation of mouse bronchopulmonary C-fibres by serotonin and allergen-ovalbumin challenge

The effect of serotonin on capsaicin-sensitive vagal C-fibre afferent nerves was evaluated in an ex vivo vagally innervated mouse lung preparation. Action potentials arising from receptive fields in the lungs were recorded with an extracellular electrode positioned in the nodose/jugular ganglion. Among the 62 capsaicin-sensitive C-fibres studied (conduction velocity ∼0.5 m s(−1)), 71% were of the nodose phenotype and 29% of the jugular phenotype. The nodose C-fibres responded strongly to serotonin and this effect was blocked with the 5-HT3-receptor antagonist ondansetron. Using single cell RT-PCR, we noted that the vast majority of nodose neurons retrogradely labelled from the lung, expressed 5-HT3 receptor mRNA. The jugular C-fibres also responded strongly to serotonin with action potential discharge, but this effect was not inhibited by ondansetron. Lung-specific jugular neurons did not express 5-HT3 receptor mRNA but frequently expressed 5-HT1 or 5-HT4 receptor mRNA. Mast cells are the major source of serotonin in healthy murine airways. Ovalbumin-induced mast cell activation in actively sensitized lungs caused action potential discharge in jugular but not nodose C-fibres. The data show that vagal C-fibres in the respiratory tract of the mouse are strongly activated by serotonin. Depending on the C-fibre subtype both 5-HT3 and non-5-HT3 mechanisms are involved