Alpha-adrenergic Receptors Research Articles

Pharmacologically Induced Ex Copula Ejaculation in Horses and Donkeys.

Pharmacologically induced ex copula ejaculation is a method used for collection of semen when the traditional methods of semen collection are not feasible. Common indications for this method include health issues that either preclude the physical act of mating or result in impaired erection and ejaculation. The method also offers an alternative when there is a lack of equipment and facilities required for semen collection using the conventional artificial vagina method. A variety of pharmacological protocols for ex copula ejaculation in stallions have been evaluated in both research and clinical settings with no serious side-effects reported. In general, these protocols included tricyclic antidepressants, alpha-2 adrenergic receptor agonists, and smooth muscle stimulators, either individually or in combination. Although there is a lot of variation in the ejaculatory rates among studies, a combination of imipramine and xylazine appears to be an effective option for inducing ejaculation in stallions. In cases where this protocol is not successful, collections should be reattempted using a combination of imipramine, detomidine, and oxytocin. Regardless of the protocol used, a quiet environment with minimal disturbance is associated with a better outcome. In contrast to the body of literature available on pharmacologically induced ex copula ejaculation in horses, only a few studies have been published so far on this topic in donkeys. Further studies are warranted to investigate whether pharmacologically induced ex copula ejaculation is an effective method of semen collection in jacks and to compare different pharmacological protocols for inducing ejaculation in jacks.

Transcriptomic profiling in mild cognitive impairment using peripheral blood gene co‐expression networks

AbstractBackgroundIn an effort towards AD prodromal risk assessment, precision medicine and biomarker development, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data by constructing gene‐coexpression networks from differentially expressed genes between normal controls and MCI subjects.MethodData from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, ImaGene) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52) (Table 1). Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. In a preliminary analysis we selected 2062 genes (out of HOW MANY) which were significantly differentially expressed between normal controls and MCI (two sample t‐test, pfdr<0.05). Gene‐coexpression networks were built by creating correlation matrices of the differentially expressed mRNA values. Network backbones were then built using the shortest path computation to remove redundancy and identify important edges. Hierarchical clustering was performed on the co‐expression matrix to identify important communities or clusters within the network. We identified the strongest cluster associated with amnestic MCI phenotype (pfdr<0.0001) by using the first principal component of the cluster as the eigen gene. The genes within the cluster and edges within the backbone were investigated.ResultUpon backbone computation, the number of edges compared to original correlation matrix were significantly reduced (Figure 1). Hierarchical clustering yielded 42 clusters of genes. One cluster (eigen gene) had the strongest association with amnestic MCI phenotype (r=0.45, pfdr<0.0001). This cluster consisting of 46 genes warrants further investigation for specific function and interactions with other nodes in the cluster backbone. Two of the driver genes ADRA1A and ARHGAP4 were involved in noradrenergic receptor signaling pathway and PDGF signaling pathway, both of which are dysregulated in AD pathogenesis.ConclusionA large noisy transcriptomic data was reduced to a critical number of mRNA measures from peripheral blood. The backbone method pruned the gene coexpression network significantly. The cluster analysis identified a set of genes which had highly significant association with amnestic MCI. This approach can also help build models for risk assessment, gene therapy and help identify novel therapeutic targets/ dysregulated pathways.

Segmental Arterial Mediolysis: A Multiguised Vasospastic Arteriopathy with Collateral Mesangial Cell Hyperplasia and Cardiac Toxicity Generated by Norepinephrine and Hyperdense Adrenoceptors Alone or by Crosstalk with Other Pressor Agents.

Segmental arterial mediolysis (SAM), an uncommon vasospastic arteriopathy occurring in the muscular arteries innervated by the peripheral sympathetic nervous system, usually presents with catastrophic abdominal and retroperitoneal hemorrhages in elderly patients. SAM is initiated by the coupling of norepinephrine to plastically derived hyperdense foci of alpha-1 adrenergic receptors on the sarcolemma of arterial muscle. This ligand is created by stimuli signaled by iatrogenic sympathomimetic agonists, some beta-2 agonists, or an excessive release of adrenal catecholamines. Coupling of this ligand with cytoplasmic heterotrimeric Gq protein excessively signals a cascade of biochemical events generating two principal lesions of injurious-phase SAM—the shearing of the outer media from the adventitia and an overload of cytoplasmic calcium ions toxic to mitochondria causing mediolysis and/or apoptosis. The massive hemorrhages are caused by ruptured gap aneurysms created by the transmedial loss of the medial muscle. A norepinephrine-directed reparative response rapidly develops either resolving angiographic injurious lesions or creating a body of vascular disorders, the new guises of SAM with ischemic clinical profiles. These present in the epicardial, vertebral, intestinal, and retroperitoneal arteries, often in younger females as fibromuscular dysplasia, dissecting hematomas, and persistent aneurysms. Norepinephrine can crosstalk with other pressor agents to create SAM lesions—serotonin with idiopathic pulmonary hypertension and persistent pulmonary hypertension in the newborn, histamine in spontaneous coronary artery dissections with eosinophilia, and endothelin-1 in a field effect generated by SAM that creates venous fibromuscular dysplasia. Norepinephrine also participates in the collateral development of mesangial hyperplasia with focal segmental glomerulosclerosis and myocardial mediolysis and apoptosis in subjects with markedly elevated heart rates. Conclusion. Norepinephrine coupling with plastically elevated alpha-1 adrenoceptor or other pressor agents generates SAM, a histologically recognizable vasospastic arteriopathy, that with repair is transformed into several different standardized arterial diseases that alter SAM's clinical profile from a hemorrhagic to an ischemic disorder.

Effect of Noradrenaline on the Facial Stimulation-Evoked Mossy Fiber-Granule Cell Synaptic Transmission in Mouse Cerebellar Cortex.

Noradrenaline is an important neuromodulator in the cerebellum. We previously found that noradrenaline depressed cerebellar Purkinje cell activity and climbing fiber–Purkinje cell synaptic transmission in vivo in mice. In this study, we investigated the effect of noradrenaline on the facial stimulation-evoked cerebellar cortical mossy fiber–granule cell synaptic transmission in urethane-anesthetized mice. In the presence of a γ-aminobutyrateA (GABAA) receptor antagonist, air-puff stimulation of the ipsilateral whisker pad evoked mossy fiber–granule cell synaptic transmission in the cerebellar granular layer, which expressed stimulus onset response, N1 and stimulus offset response, N2. Cerebellar surface perfusion of 25 μM noradrenaline induced decreases in the amplitude and area under the curve of N1 and N2, accompanied by an increase in the N2/N1 ratio. In the presence of a GABAA receptor blocker, noradrenaline induced a concentration-dependent decrease in the amplitude of N1, with a half-maximal inhibitory concentration of 25.45 μM. The noradrenaline-induced depression of the facial stimulation-evoked mossy fiber–granule cell synaptic transmission was reversed by additional application of an alpha-adrenergic receptor antagonist or an alpha-2 adrenergic receptor antagonist, but not by a beta-adrenergic receptor antagonist or an alpha-1 adrenergic receptor antagonist. Moreover, application of an alpha-2 adrenergic receptor agonist, UK14304, significantly decreased the synaptic response and prevented the noradrenaline-induced depression. Our results indicate that noradrenaline depresses facial stimulation-evoked mossy fiber–granule cell synaptic transmission via the alpha-2 adrenergic receptor in vivo in mice, suggesting that noradrenaline regulates sensory information integration and synaptic transmission in the cerebellar cortical granular layer.

Synchronized cluster firing, a distinct form of sensory neuron activation, drives spontaneous pain

Spontaneous pain refers to pain occurring without external stimuli. It is a primary complaint in chronic pain conditions and remains difficult to treat. Moreover, the mechanisms underlying spontaneous pain remain poorly understood. Here we employed invivo imaging of dorsal root ganglion (DRG) neurons and discovered a distinct form of abnormal spontaneous activity following peripheral nerve injury: clusters of adjacent DRG neurons firing synchronously and sporadically. The level of cluster firing correlated directly with nerve injury-induced spontaneous pain behaviors. Furthermore, we demonstrated that cluster firing is triggered by activity of sympathetic nerves, which sprout into DRGs after injury, and identified norepinephrine as a key neurotransmitter mediating this unique firing. Chemogenetic and pharmacological manipulations of sympathetic activity and norepinephrine receptors suggest that they are necessary and sufficient for DRG cluster firing and spontaneous pain behavior. Therefore, blocking sympathetically mediated cluster firing may be a new paradigm for treating spontaneous pain.

Putative Role of Monoaminergic Systems in Antidepressant and Anxiolytic Effects of Naringin in Mice: An Interaction Study with Receptor Antagonists

Aim: Stress-related disorders like depression and anxiety represent one of the greatest therapeutic challenges globally. Although previous studies have revealed the antidepressant-like potentials of naringin, the neurotransmitter receptor interaction mechanisms of action have not been studied, hence, this study was carried out to evaluate the role of neurotransmitter-receptor antagonists in the antidepressant-like effects of naringin in mice.
 Method: Male Swiss mice were subjected to chronic unpredictable mild stress (CUMS) apart from mice in the control group. The mice were then pretreated with different neurotransmitter antagonists; metergoline (4 mg /kg i.p.), a 5-HT1 - and 5-HT2 -receptor antagonist; propranolol; (0.2 mg/kg i.p.), β1,2-noradrenoceptor antagonist or haloperidol (0.2 mg/kg i.p.), D 2 -dopaminergic receptor antagonists prior to the administration of naringin or vehicle (10 mL/kg). The antidepressant-like and anxiolytic effects of naringin were evaluated 30 min later using the tail suspension test (TST), open-field test (OFT), sucrose preference test (SPT) and elevated plus maze (EPM) tests paradigms.
 Results: Administration of naringin following CUMS significantly decrease immobility time and locomotion activity in TST and OFT respectively, relative to control while increasing preference to sucrose in SPT, open arm entries as well as time spent in open arm in EPM, relative to control suggesting antidepressant-like property. Pretreatment with metergoline, propranolol, and haloperidol following CUMS increased immobility time in TST, locomotor activity in OFT and IOAA in the EPM. Reduced preference for sucrose in SPT, open arm entry and duration in EPM relative to control (p < 0.05), however, these effects were attenuated by naringin.
 Conclusion: These findings suggest that the antidepressant-like activity exhibited by naringin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the anxiolytic effect might involve interaction with both 5-HTergic and noradrenergic receptors.

Presynaptic Release-Regulating Alpha2 Autoreceptors: Potential Molecular Target for Ellagic Acid Nutraceutical Properties.

Polyphenol ellagic acid (EA) possesses antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, making it an interesting multi-targeting profile. EA also controls the central nervous system (CNS), since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into the TM5 area, close to S200 and S204, which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in a yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

Anti-inflammatory and antipyretic potential of Arbutus andrachne L. methanolic leaf extract in rats

Objective: To explore the anti-inflammatory and antipyretic effects of methanolic leaf extract from Arbutus andrachne and its mechanism of action. Methods: Paw edema was induced by intraplantar (i.pl.) injection of λ-carrageenan (1% w/v, 100 μL/paw) while pyrexia was evoked by intraperitoneal (i.p.) injection of 20% baker's yeast (20 mL/kg body wt) in male Wistar rats. The anti-inflammatory and antipyretic effects of Arbutus andrachne methanolic leaf extract were explored by injecting rats with different doses of the plant extract (150, 300, and 600 mg/kg body wt, i.p.). Selective antagonists for transient receptor potential vanilloid-1 (TRPV1), cannabinoid receptor 1 (CB1), and alpha-2 adrenergic receptor (a2-AR) were used to unravel the extracts’ mechanism of action. Blood samples were collected from the heart of rats to measure the levels of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) by enzyme-linked immunosorbent assay. Results: The extract exhibited potent anti-inflammatory activity by decreasing paw thickness and IL-6 levels. In addition, yeast-evoked pyrexia was attenuated by the extract treatment via TRPV1 and CB1 receptors and a reduction in PGE2 levels. No significant effects were found for a2-AR. Moreover, the rats that received the plant extract demonstrated similar responses to the positive control group. Conclusions: Arbutus andrachne can be a good candidate for treating inflammation and pyrexia and should be further investigated.

Evaluation of Vascular Pulse Contour Indices over the Physiological Blood Pressure Ranges in an Anesthetized Porcine Model.

A series of physiological measures can be assessed from the arterial pulse waveform, which is beneficial for cardiovascular health diagnosis, monitoring, and decision making. In this work, we have investigated the variations in regional pulse wave velocity (PWVR) and other pulse waveform indexes such as reflected wave transit time (RWTT), augmentation index (Alx), ejection duration index (ED), and subendocardial viability ratio (SEVR) with blood pressure (BP) parameters and heartrate on a vasoconstrictor drug-induced porcine model. Two healthy female (nulliparous and non-pregnant) Sus scrofa swine (~ 80 kg) was used for the experimental study. The measurement system consists of a catheter-based system with two highly accurate pressure catheters placed via the sheath at the femoral and carotid artery for acquiring and recording the pressure waveforms. The pulse waveform indexes were extracted from these recorded waveforms. Results from the pulse contour analysis of these waveforms demonstrated that Phenylephrine, as a post-synaptic alpha-adrenergic receptor agonist that causes vasoconstriction, produced a significant increment in the carotid BP parameters and heartrate. Due to the drug's effect, the PWVR and SEVR were significantly increased, whereas the RWTT, AIx index and ED index significantly decreased.Clinical Relevance- This experimental study provides the usefulness of the pulse contour analysis and estimation of various pulse waveform indexes for cardiovascular health screening and diagnosis.

Bombax costatum enhances piroxicam's efficacy: Possible involvement of alpha-2 adrenergic receptor, opioidergic and arachidonic pathways

With increasing drug-herb combination and widespread use of Bombax costatum as analgesic in Africa, this research studies effects of Bombax costatum on piroxicam's efficacy and possible mechanisms of antinociception. In efficacy studies, four groups of mice were respectively treated with 1mL/kg distilled water, 400mg/kg Bombax costatum, 20mg/kg piroxicam and a combination of both. Acetic acid and hot plate were used to induce pain in mice while prostaglandin-E2 and formalin were used to induce inflammation in rats. For mechanistic studies, different groups of mice were treated intraperitoneally with 2mg/kg naloxone, 1mg/kg yohimbine, 20mg/kg propranolol, 5mg/kg glibenclamide and 1mg/kg prazosin respectively. Two other groups were treated orally with 1mL/kg of the vehicle and 400mg/kg Bombax costatum respectively. 60minutes later, 10mL/kg of 0.6% acetic acid was administered via the intraperitoneal route and number of writhes were observed for 10minutes. Concurrent administration of Bombax costatum and piroxicam decreased the number of writhes significantly (P≤0.001), increased reaction time with decreased paw diameter in comparison to control. Additionally, this drug-herb combination showed enhanced anti-nocipective efficacy than when administered singly. Also, pre-treatment with yohimbine and naloxone significantly (P≤0.01) inhibited the antinociceptive activities of Bombax costatum. Bombax costatum posses antinociceptive and anti-inflammatory activities and may involve α-2 adrenergic receptor, opioidergic and arachidonic pathways. In addition, Bombax costaum augments the efficacy of piroxicam and could be of clinical benefits if studied on man.

Potential action on the central nervous system of neroli oil extracted from Citrus aurantium

The essential oil from C. aurantium has been widely studied due to its potential anxiolytic action on several receptors in the Central Nervous System (CNS). Although it presents variations in its phytochemical composition depending on its origin, we can highlight that many compounds remain present, such as linalool that demonstrated antagonistic activity on glutamatergic receptors, possible inhibitory action of noradrenaline and serotonin receptors, besides the ability to activate GABA receptors in association with some flavonoids present in the oil. It is globally known that the underlying pathology called anxiety influences worldwide as an antecedent of conflicting psychological and physical disorders, which are associated with various neuronal disorders. In this regard, the oil extracted from C. aurantium flowers shows a potential therapeutic application for the treatment of anxiety disorders. However, more studies are needed to elucidate its complete role on the CNS and to verify and prove its safety and efficacy profile.

Liquid chromatography-tandem mass spectrometry and confirmation by liquid chromatography-high-resolution mass spectrometry hair tests to evidence use of tizanidine by racing cyclists.

Tizanidine, an imidazoline derivative close to clonidine, is a central alpha-2 adrenergic receptor agonist. Therapeutically, the drug is used as a muscle relaxant under the trade names Sirdalud™ or Zanaflex™. The drug is not prohibited by the World Anti-Doping Agency but, for therapeutic purposes, can only be obtained via a nominative temporary use authorization. The French public health police requested the laboratory to test for tizanidine in head hair specimens collected from international racing cyclists. Using Liquid chromatography-tandem mass spectrometry (LC/MS-MS) and confirmation by liquid chromatography-high-resolution mass spectrometry (LC/HRMS), after pH 9.5 borate buffer overnight incubation of 20 mg and subsequent solvents extraction, tizanidine was identified in the hair of three athletes at 1.1, 3.7, and 11.1 pg/mg. This is the first evidence that tizanidine is incorporated in human hair. However, it was not possible to interpret the data in terms of doses and frequency of use due to a lack of controlled study.

Supraclavicular Brachial Plexus Block: Comparison of Varying Doses of Dexmedetomidine with Ropivacaine

Background Alpha-2 adrenergic receptor agonists have been the focus of interest nowadays as an adjuvant to local anesthesia due to its excellent sedative, analgesic, antihypertensive, anesthetic sparing and hemodynamic stabilizing properties. The ideal dose of dexmedetomidine for brachial plexus block is matter of debate.
 Objective To find the appropriate minimal dose of dexmedetomidine with desired clinical effects and minimal side-effects, we compared different doses (25 mcg, 50 mcg, 75 mcg and 100 mcg) of dexmedetomidine as an adjuvant to ropivacaine.
 Method One hundred fifty patients of ASA I and II, aged (18-60) years, weighing (50-60) kilograms undergoing upper limb surgeries under brachial plexus block were enrolled in this prospective, double blind, randomized control study. Patients in all group received 19 ml of 0.5% ropivacaine in common. In addition; group RD25, RD50, RD75 and RD100 received 25 mcg, 50 mcg, 75 mcg and 100 mcg of dexmedetomidine diluted in 1 ml of normal saline (NS) respectively whereas group RD00 received only 1 ml of NS. The duration of analgesia was the primary outcome whereas block characteristics, hemodynamic parameters, oxygen saturation, sedation score and adverse effects were taken as secondary outcome. Statistical analysis was done using ANOVA test, Chi-square test and Scheffe’s multiple comparison tests.
 Result The demographic profile and baseline hemodynamic variables were comparable in all five groups. Increasing dose of dexmedetomidine showed significant improvement in block characteristics but associated with increase in sedation and incidence of bradycardia.
 Conclusion We conclude that dexmedetomidine 50 mcg would be an appropriate dose as adjuvant to local anesthesia in brachial plexus block.

Pathogenetic features of acute naphazoline poisoning in children

Introduction: Acute poisoning by nasal decongestants is an important issue in pediatrics due to physiological and anatomical characteristics of the child’s body and pharmacokinetics of drugs in early childhood.
 Epidemiology: The number of poisonings by this group of drugs ranged from 4% to 39% during the period from 2000 to 2018. All the studies reported that the most severe degree of intoxication was observed in children aged 1–3 years.
 Mechanism of action of nasal decongestants: The peculiarity of selective alpha2-adrenergic agonists is that when taken orally, misused or overdosed, they lose their selectivity for the target receptor. As a result, the drug causes acute poisoning and most often this effect occurs in children and adolescents.
 Clinical features and diagnostic criteria: Clinical signs of acute poisoning can appear both as a result of an overdose of the nasal decongestants and due to a therapeutic use of the drug according to the instruction. The symptoms are manifested by hypothermia, skin pallor, bradycardia, arterial hypotension, profuse sweating, and acrocyanosis.
 Imidazoline receptors and new opportunities: It is assumed that toxic effect of topical decongestants occurs not only by activation of alpha2-adrenergic receptors, but also through their influence on the selective imidazoline receptors. Based on the structure of these drugs, it is assumed that imidazoline receptors are the primary binding site for these drugs.
 Conclusion: Understanding the described mechanisms of alpha2-adrenergic agonist action and peculiarities of the child’s symptoms in acute poisoning is necessary for the timely diagnosis and selection of the correct treatment strategy.

The Anticonvulsant Effects of Alpha-2 Adrenoceptor Agonist Dexmedetomidine on Pentylenetetrazole-Induced Seizures in Rats

Alpha2-adrenoreceptor (α2-AR) is a noradrenergic receptor that is frequently studied for modulation of seizure activity. However, the precise role of this receptor agonists in regulating seizure activity is still unclear. Our aim in this study was to investigate the effects of α2-AR agonist dexmedetomidine (DEX) and atipamezole (α2-AR antagonist, ATI) on seziures in rats. In the study, 32 adult male Wistar Albino rats (weighing 220-260g) were used. To induce seizures in rats, pentylenetetrazole (PTZ, 35mg/kg) was injected intraperitoneally (i.p.) and seizure stages were determined according to the Racine scale. After induction of seizures, DEX (0.1mg/kg, i.p.) and ATI (1mg/kg, i.p.) were administered to rats and their effects determined on seizures. GABA levels of the brain hippocampal tissue sample were measured using an ELISA kit and c-Fos positive cells of the dentate gyrus and hippocampal regions were quantitatively analyzed with Image J software. The results showed that DEX decreased the seizure stages according to the Racine scale, significantly prolonged the onset time of first myoclonic jerk (FMJ) and reduced the number of spikes and percentage seizure duration (p < 0.05). In contrast, ATI increased the seizure stage, the number of spikes and percentage seizure duration. The hippocampal GABA level was significantly decreased in rats with only PTZ injection (p < 0.05). In addition, DEX reduced the number of c-Fos positive cells in dentate gyrus and the hippocampal CA1 and CA3 regions. In conclusion, our findings showed that α2-AR agonist DEX had a reducing activity on PTZ-induced seizure, while α2-AR antagonist ATI facilitated seizure formation.

LB787 CLE-400: A potent alpha-2 adrenergic receptor agonist for the treatment of chronic itch

Pruritus (itch) is a major symptom of several dermatological diseases but has limited therapeutic options available. Itch stimuli are transmitted via primary sensory neurons in the skin by activating pruriceptors/nociceptors on small unmyelinated C-fibers, through the spinal cord for final processing in the brain. CLE-400 is an aqueous gel of detomidine that is being developed for the topical treatment of itch. Detomidine is a potent α2-adrenergic receptor (α2-AR) agonist. α2-AR have been shown to be expressed on skin nociceptors and their activation by topical administration of detomidine could lead to inhibition of itch neural signalling.

Noradrenergic Profile of Hippocampal Formation Theta Rhythm in Anaesthetized Rats

The present study was undertaken to identify the noradrenergic receptors underlying the production of hippocampal formation (HPC) type 2 theta rhythm. The experiments were performed on urethanized rats wherein type 2 theta is the only rhythm present. In three independent stages of experiments, the effects of noradrenaline (NE) and selective noradrenergic α and β agonists and antagonists were tested. We indicate that the selective activation of three HPC noradrenergic receptors, α1, α2 and β1, induced a similar effect (i.e., inhibition) on type 2 theta rhythm. The remaining HPC β2 and β3 noradrenergic receptors do not seem to be directly involved in the pharmacological mechanism responsible for the suppression of theta rhythm in anaesthetized rats. Obtained results provide evidence for the suppressant effect of exogenous NE on HPC type 2 theta rhythm and show the crucial role of α1, α2 and β1 noradrenergic receptors in the modulation of HPC mechanisms of oscillations and synchrony. This finding is in contrast to the effects of endogenous NE produced by electrical stimulation of the locus coeruleus (LC) and procaine injection into the LC (Broncel et al., 2020).

Liver, Renal, and Cardiovascular Failure After Unintentional Overdose of Tizanidine in a 2-Year-Old Child.

Tizanidine is a central alpha-2 adrenergic receptor agonist indicated for the treatment of spasticity in adults; however, its use in the pediatric population is considered off-label. In adults, the dose is gradually titrated until the desired reduction in muscle tone is achieved. Hypotension is a frequent adverse effect, but impaired liver function is not characteristic of alpha-2 adrenergic agonist overdose. We report a 2-year-old male affected with spastic quadriplegia (treated with clonazepam and tizanidine) and dysphagia (he was fed by nasogastric tube). Two days before admission caregivers ran out of clonazepam so they increased the tizanidine dose from 0.15 mg/kg/day to 1.6 mg/kg/day. Simultaneously his nasogastric tube fell out; therefore, he was unable to maintain proper oral nutrition and hydration. He presented to the emergency department hemodynamically unstable, with impaired consciousness and signs of severe dehydration. Blood tests revealed hepatic dysfunction without cholestasis and renal dysfunction. He was transferred to the pediatric intensive care unit. Treatment was mainly supportive, apart from tizanidine discontinuation. Metabolic and infectious diseases were ruled out so he was finally diagnosed as having liver, renal, and cardiovascular failure after tizanidine overdose, worsened by dehydration. His clinical status improved, and after 3 weeks he was discharged from the hospital, receiving clonidine instead of tizanidine to treat spasticity. Tizanidine overdose can result in serious complications that can be worsened because of patient comorbidities.

Effects of highly selective sympathectomy on neurogenic bowel dysfunction in spinal cord injury rats

Neurogenic bowel dysfunction, including hyperreflexic and areflexic bowel, is a common complication in patients with spinal cord injury (SCI). We hypothesized that removing part of the colonic sympathetic innervation can alleviate the hyperreflexic bowel, and investigated the effect of sympathectomy on the hyperreflexic bowel of SCI rats. The peri-arterial sympathectomy of the inferior mesenteric artery (PSIMA) was performed in T8 SCI rats. The defecation habits of rats, the water content of fresh faeces, the intestinal transmission function, the defecation pressure of the distal colon, and the down-regulation of Alpha-2 adrenergic receptors in colon secondary to PSIMA were evaluated. The incidence of typical hyperreflexic bowel was 95% in SCI rats. Compared to SCI control rats, PSIMA increased the faecal water content of SCI rats by 5–13% (P < 0.05), the emptying rate of the faeces in colon within 24 h by 14–40% (P < 0.05), and the defecation pressure of colon by 10–11 mmHg (P < 0.05). These effects lasted for at least 12 weeks after PSIMA. Immunofluorescence label showed the secondary down-regulation of Alpha-2 adrenergic receptors after PSIMA occurred mainly in rats’ distal colon. PSIMA mainly removes the sympathetic innervation of the distal colon, and can relieve the hyperreflexic bowel in rats with SCI. The possible mechanism is to reduce the inhibitory effect of sympathetic activity, and enhance the regulatory effect of parasympathetic activity on the colon. This procedure could potentially be used for hyperreflexic bowel in patients with SCI.

Pharmacology of Drugs Used as Stimulants.

Psychostimulant, cardiovascular, and temperature actions of stimulants involve adrenergic (norepinephrine), dopaminergic (dopamine), and serotonergic (serotonin) pathways. Stimulants such as amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 to inhibit reuptake of neurotransmitter or cause release by reverse transport. Stimulants may have additional effects involving pre- and postsynaptic/junctional receptors for norepinephrine, dopamine, and serotonin and other receptors. As a result, stimulants may have a wide range of possible actions. Agents with cocaine or MDMA-like actions can induce serious and potentially fatal adverse events via thermodysregulatory, cardiovascular, or other mechanisms. MDMA-like stimulants may cause hyperthermia that can be life threathening. Recreational users of stimulants should be aware of the dangers of hyperthermia in a rave/club environment.