Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.

Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments for pain as a complement to opioid-based treatments. Here we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in male and female mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by CB1 receptors (CB1Rs) within the VTA as VTA CB1R conditional knockout, counteracts JZL184's effects. Conversely, pharmacologically enhancing the levels of the other eCB, anandamide (AEA), by inhibition of fatty acid amide hydrolase (FAAH) has no effect on opioid reward or analgesia. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related nucleus accumbens (NAc) activity and DA neurotransmission. Together these findings reveal that 2-AG counteracts the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.

Electrophysiological Evidence for Anti-epileptic Property of Taurine.

Taurine, 2-aminoethanesulfonic acid, is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Several lines of evidence suggest that taurine may function as a potent inhibitory neuromodulator that regulate neuronal activity in many cerebral areas. Parenteral injection of kainic acid (KA), a glutamate receptor agonist, causes severe and stereotyped behavioral convulsions in mice and is used as a rodent model for human temporal lobe epilepsy. In the adult brain, inhibitory GABAergic interneurons modulate the activity of principal excitatory cells via their GABAA receptors and thus adjust excitatory output of neuronal circuits. The goal of this study was to examine the potential anti-convulsive effects of the neuro-active amino acid taurine, in the mouse model of limbic seizures. We used the glutamic acid decarboxylase (GAD) inhibitor isoniazid (100 mg.kg-1, s.c.) which induces seizures by interfering with GABA synthesis through inhibition of GAD activity followed by kainic acid (5 mg.kg-1, s.c.) a glutamate receptor agonist which is commonly used to induce limbic seizures.Using intracerebral recordings of field potentials found that taurine (43 mg.kg-1, s.c.) had a significant anti-epileptic effect when injected prior to isoniazid and KA. Furthermore, injection of taurine to a mouse undergoing limbic seizure completely stopped burst population spikes and restored neuronal firing to its baseline. Therefore, taurine is potentially capable of treating seizure-associated brain damage.

In Vivo Sex-Dependent Effects of Perinatal Pb2+ Exposure on Pilocarpine-Induced Seizure Susceptibility and Taurine Neuropharmacology.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.

Hyperreflexia and enhanced ripple oscillations in the taurine-deficient mice.

In this study, we examined neuronal excitability and skeletal muscle physiology and histology in homozygous knockout mice lacking cysteine sulfonic acid decarboxylase (CSAD-KO). Neuronal excitability was measured by intracerebral recording from the prefrontal cortex. Skeletal muscle response was measured through stretch reflex in the ankle muscles. Specifically, we measured the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle was stretched at various speeds ranging from 18 to 18,000° s-1. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We also measured the same parameter in anesthetized mice. We found that at each velocity, the CSAD-KO mice generated more tension and exhibited higher EMG responses. To evaluate if the enhanced response was due to neuronal excitability or changes in the passive properties of muscles, we anesthetize mice to eliminate the central component of the reflex. Under these conditions, CSAD-KO mice still exhibited an enhanced stretch reflex response, indicating ultrastructural alterations in muscle histology. Consistent with this, we found that sarcomeres from CSAD-KO muscles were shorter and thinner when compared to control sarcomeres. Neuronal excitability was further investigated using intracerebral recordings of brain waves from the prefrontal cortex. We found that extracellular field potentials in CSAD-KO mice were characterized by reduced amplitude of low-frequency brain waves (delta, theta, alpha, beta and gamma) and increased in the high low-frequency brain waves (slow and fast ripples). Increased slow and fast ripple rates serve as a biomarker of epileptogenic brain. We have previously shown that taurine interacts with GABAA receptors and induces biochemical changes in the GABAergic system. We suggest that taurine deficiency leads to alterations in the GABAergic system that contribute to the enhanced stretch reflex in CSAD-KO mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.

Taurine Enhances Stretch Reflex Excitability.

The purpose of this study was to characterize the effects of taurine (supplementation and acute injection) on the stretch reflex in the ankle muscles, and in particular to compare the effects of chronic taurine supplementation versus acute injection on the muscle tension, amplitude of electromyogram and velocity of muscle response. Stretch reflex responses were evoked using a specialized stretching device designed for mice. The triceps surae muscle of an awake mouse was stretched at various speeds ranging from 500 to 500,000° per second. A transducer recorded the muscle resistance at each velocity and the corresponding EMG. We found that at each velocity, the taurine-fed mice generated more tension and exhibited a higher EMG response. Acute taurine injection did not affect the tension but significantly reduced the EMG. To evaluate if the enhances response was due to neuronal excitability of changes in the passive properties of the muscles, we anesthetize the mice to eliminate the central component of the reflex. Under these conditions, taurine-fed mice still exhibited an enhanced stretch reflex response. We have previously shown that taurine-fed mice have reduced expression of GABAA receptors and other biochemical changes in the GABAergic system that are consistent with hyper-excitability. GABAA receptor is a major component of the inhibitory (GABAergic) system and its reduced expression probably contributes to the enhanced stretch reflex in these mice through biochemical mechanisms that involve alterations not only at the spinal level but also at the cortical level.