piperidines and Reflex--Abnormal

To compare spectral analysis of the electrocardiogram (ECG) with mean arterial pressure (MAP) and heart rate (HR) monitoring in the detection of autonomic hyperreflexia (AHR) induced by sacral root stimulation.. Ten spinal cord injured patients scheduled for implantation of a sacral root stimulator for bladder retention were included. Under target controlled anesthesia with propofol 4 micro g*mL(-1) and remifentanil 4 ng*mL(-1), the patients were placed in the knee chest position. The sacral roots were exposed by laminectomy (L2-S1) and their function assessed by electrostimulation under urodynamic and cardiovascular monitoring. Online power spectrum densities were calculated from the ECG R-R interval by the MemCalc(TM) software using the maximum entropy method. Low frequency (LF: 0.04-0.15 Hz) and high frequency (HF: 0.15-0.4 Hz) spectra were associated with sympathetic and parasympathetic activities respectively. The most extreme value of each variable was noted before and during each stimulation. A difference ( triangle up ) of more than 10% signified AHR. The comparison ( triangle up LF vs triangle up MAP and triangle up HF vs triangle up HR) was done by a concordance test with a kappa coefficient (k): -1 = total discordance to 1 = total concordance.. AHR was detected in six patients as an increase in LF and MAP (n = 4); an increase in LF, HF, MAP with a decrease in HR (n = 2). The detection delay was 5.3 +/- 1 sec (LF, HF) and 10.4 +/- 1.2 sec (MAP and HR). Concordance was 85% (LF vs MAP: k = 0.7) and 90% (HF vs HR: k = 0.8).. AHR induced by sacral root stimulation is detected by spectral analysis of the ECG earlier than MAP and HR. Other studies are needed to confirm these results.

Topics: Adolescent; Adult; Anesthetics, Intravenous; Autonomic Dysreflexia; Blood Pressure; Electric Stimulation; Electrocardiography; Female; Heart Rate; Humans; Laminectomy; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Reflex, Abnormal; Remifentanil; Spinal Cord Injuries; Spinal Nerve Roots; Urinary Incontinence; Urodynamics

AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects.. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ. For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

Topics: Adamantane; Aggression; Animals; Behavior, Animal; Binding, Competitive; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabis; Catalepsy; Dopamine; Dronabinol; Humans; In Vitro Techniques; Indazoles; Indoles; Male; Mice; Motor Activity; Naphthalenes; Nucleus Accumbens; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex, Abnormal; Seizures

JWH-018 is a synthetic CB1 and CB2 agonist illegally marketed as products named "Spice" or "herbal blend" for its psychoactive effects which are much higher than those produced by cannabis. In the last year, the European Monitoring Centre for Drugs and Drug Addiction reported to the Italian National Early Warning System the seizure of plant material containing new halogenated derivatives of JWH-018 (JWH-018 Cl and JWH-018 Br). The present study aimed to investigate the in vitro and in vivo activity of these two new synthetic cannabinoids in mice. In vitro competition binding experiments performed on mouse and human CB1 receptors revealed a high affinity and potency of the halogenated compounds. Synthetic cannabinoids (0.01-6 mg/kg i.p.) impaired motor activity and induced catalepsy in mice and their effects were more severe with respect to those evoked by Δ(9)-THC. Moreover, they increased the mechanical and thermal pain threshold and induced a marked hypothermia. It is interesting to note that whereas high doses of JWH-018 cause seizures, myoclonia and hyperreflexia, the halogenated compounds, in particular JWH-018Br, were less effective. Behavioral and neurological changes were prevented by the selective CB1 receptor antagonist AM 251. These data demonstrate for the first time that JWH-018 Cl and JWH-018 Br act similarly to JWH-018 while inducing less convulsive episodes and myoclonias. These data support the hypothesis that the halogenated compounds may have been introduced onto market to produce similar intoxicating effects as JWH-018 while causing less side effects.

Topics: Animals; Binding, Competitive; Cannabinoid Receptor Agonists; Cannabinoids; Catalepsy; CHO Cells; Cricetulus; Halogenation; Humans; Hypothermia; Indoles; Male; Mice, Inbred ICR; Motor Activity; Naphthalenes; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex, Abnormal; Seizures

Increased afferent nerve activity may have an important role in the pathogenesis of neurogenic detrusor overactivity. We tested the efficacy of the neuokinin-2 receptor antagonist M274773 ((S)-N-[2-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydro-pyrimidin-l-yl) piperidino]butyl]-N-methylbenzamide dihydrochloride) on neurogenic detrusor overactivity after spinal cord injury in rats.. Included in this study were 48 adult Sprague-Dawley rats (Charles River, Montreal, Quebec, Canada). Six animals served as normal controls, while 32 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm neurogenic detrusor overactivity, while another 12 served as paraplegic controls. The remaining 24 paraplegic animals were used to test the drug and they were divided into 2 equal groups of 12. Group 1 received the drug at a dose of 0.3 mg/kg daily, while group 2 received a dose of 0.6 mg/kg daily. Each paraplegic control and treatment group was further subdivided into 2 subgroups of 6 rats each. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury.. Three weeks after spinal cord injury neurogenic detrusor overactivity developed in all paraplegic control animals with a mean bladder capacity +/- SD of 0.7 +/- 0.2 ml and a mean voiding pressure of 59 +/- 14.2 cm H2O. Neurogenic detrusor overactivity resolved in 50% and 83% of the animals that received M274773 for 1 week at doses of 0.3 and 0.6 mg/kg daily, respectively. Mean cystometric bladder capacity was 1.2 +/- 0.5 vs 1.3 +/- 0.4 ml and mean voiding pressure was 46.1 +/- 10.8 vs 40 +/- 9.9 cm H2O in animals that received 0.3 vs 0.6 mg/kg daily, respectively. The drug produced better urodynamic results when given for 2 weeks rather than 1 week.. M274773 is effective for neurogenic detrusor overactivity after spinal cord injury in the rat. It may provide an alternative clinical treatment option for neurogenic detrusor overactivity and urgency/frequency syndrome. This new neurokinin-2 selective antagonist has time and dose response effects, which further suggests the potential for clinical application.

Topics: Animals; Benzamides; Dose-Response Relationship, Drug; Female; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Reflex, Abnormal; Spinal Cord Injuries; Urinary Bladder; Urinary Bladder, Neurogenic; Urodynamics

We explored whether substance P (SP) via neurokinin (NK) receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder in association with neurogenic inflammation. We evaluated ROS activity and cystometrograms as well as pelvic nervous activity in anesthetized rat bladder with SP stimulation. Our results showed that endogenous SP via NK(1), not NK(2), receptor mediated a micturition reflex. An increase in SP by electrical stimulation of the pelvic nerve or an increase in exogenous SP by intra-arterial or intrathecal administration can facilitate myogenic and neurogenic bladder contractions. Furthermore, exaggerated SP release increased ROS in the bladder and whole blood via increased mast cell degranulation, intercellular adhesion molecule expression, and leukocyte adhesion, a primary source of ROS in the inflamed bladder. Treatment with NK(1)-receptor antagonists or ROS scavengers reduced bladder intercellular adhesion molecule expression and ROS and ameliorated the hyperactive bladder response. Our study indicates that the mechanism by which SP participates in the neurogenic bladder may be complicated by its proinflammatory activity and its ability to stimulate ROS generation.

Topics: Animals; Benzamides; Biphenyl Compounds; Cell Adhesion Molecules; Dose-Response Relationship, Drug; Drug Administration Routes; Electric Stimulation; Female; Free Radical Scavengers; Muscle Contraction; Neurokinin-1 Receptor Antagonists; Pelvis; Piperidines; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Neurokinin-1; Reflex, Abnormal; Signal Transduction; Sodium Chloride; Substance P; Superoxide Dismutase; Urinary Bladder; Urinary Bladder, Neurogenic; Urination; Visceral Afferents

Cannabinoids have previously been shown to possess analgesic properties in a model of visceral hyperalgesia in which the neurotrophin, nerve growth factor (NGF), plays a pivotal role. The purpose of this study was to investigate the antihyperalgesic effects of two cannabinoids in NGF-evoked visceral hyperalgesia in order to test the hypothesis that endocannabinoids may modulate the NGF-driven elements of inflammatory hyperalgesia. Intra-vesical installation of NGF replicates many features of visceral hyperalgesia, including a bladder hyper-reflexia and increased expression of the immediate early gene c fos in the spinal cord. We investigated the action of anandamide and palmitoylethanolamide (PEA) on these parameters. Both anandamide (at a dose of 25 mg/kg) and PEA (at a dose of 2.5 mg/kg) attenuated the bladder hyper-reflexia induced by intra-vesical NGF. The use of cannabinoid CB1 receptor (SR141617A) and CB2 receptor (SR144528) antagonists suggested that the effect of anandamide was mediated by both CB1 and CB2 cannabinoid receptors whilst the action of PEA was via CB2 (or CB2-like) receptors only. Furthermore, anandamide (25 mg/kg) and PEA (2.5 mg/kg) reduced intra-vesical NGF-evoked spinal cord Fos expression at the appropriate level (L6) by 35 and 43%, respectively. However, neither CB1 nor CB2 receptor antagonists altered the action of anandamide. PEA-induced reduction in Fos expression was abrogated by SR144528. These data add to the growing evidence of a therapeutic potential for cannabinoids, and support the hypothesis that the endogenous cannabinoid system modulates the NGF-mediated components of inflammatory processes.

Topics: Amides; Animals; Arachidonic Acids; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Endocannabinoids; Ethanolamines; Female; Hyperalgesia; Nerve Growth Factor; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Reflex, Abnormal; Rimonabant; Spinal Cord; Urinary Bladder; Visceral Afferents

To see whether a recently characterized model of bacterial toxin-induced urinary bladder inflammation (Stein et al., J. Urol. 155, 1133-1138, 1996) is associated with detrusor hyperreflexia, and whether endogenous tachykinins acting through NK2 or NK1 receptors were involved in this model.. The bladder of urethane-anesthetized male Wistar rats was cannulated through the dome. Intravesical administration of protamine sulfate (PS, 10 mg./ml./rat) or vehicle for 1 hour was followed by the intravesical administration of E. coli lipopolysaccharide (LPS, 1 mg./ml./rat) or vehicle for 1 hour. Cystometries (50 microl./min.) were performed 3.5 hours after the exposure to LPS. MEN 11,420, a peptide tachykinin NK2 receptor antagonist, was administered before cystometries or, in a separate group of animals, during cystometries. The effect of SR 140,333, a non-peptide NK1 receptor antagonist, was also assessed in the presence or absence of MEN 11,420. The urodynamic effects of PS + LPS were also tested in capsaicin-pretreated rats.. Unlike PS or LPS alone, the intravesical administration of PS + LPS induced detrusor hyperreflexia. In PS + LPS treated animals during nonstop cystometries, the intermicturition interval was decreased by about 50% as compared to vehicle-pretreated rats. A quantitatively similar reduction in the bladder capacity was also observed. MEN 11,420 (100 nmol./kg., i.v.) restored the intermicturition interval in PS + LPS-pretreated rats at the level of controls by increasing the bladder capacity, whereas it had no effect in vehicle-pretreated rats. SR 140,333 (1 micromol./kg., i.v.) neither modified urodynamic parameters in controls and in PS + LPS-treated rats nor altered the effect of MEN 11,420 in these groups. Capsaicin pretreatment (164 micromol./kg., s.c., 4-5 days before) induced a two-fold increase of the bladder capacity in control rats and prevented PS + LPS-induced bladder hyperreflexia.. The intravesical administration of PS + LPS produces the activation of capsaicin-sensitive afferents. Endogenous tachykinins released from these fibers act through NK2 receptors to induce detrusor hyperreflexia.

Topics: Animals; Escherichia coli; Lipopolysaccharides; Male; Muscle, Smooth; Peptides, Cyclic; Piperidines; Protamines; Quinuclidines; Rats; Rats, Wistar; Receptors, Tachykinin; Reflex, Abnormal; Urinary Bladder

An intraluminal balloon was used to study the peristaltic reflex, which is mediated by the intrinsic nerves of the oesophagus. Serial balloon distension was performed in nine asymptomatic volunteers and 133 patients with oesophageal symptoms. Eight of the volunteers had a normal response with proximal stimulation and distal inhibition of motility. Only 42 patients (31.6 per cent) had a normal response. The commonest abnormal response (39.1 per cent) was some form of failure of the distal inhibitory reflex. Other patterns of abnormality were an unresponsive oesophagus (15.8 per cent) with no motility change during balloon inflation, or spasm (13.5 per cent) proximal to the balloon. These alterations of secondary peristaltic activity suggest that there are abnormalities of the intrinsic (enteric) nerves of the oesophagus. Different abnormalities were found in patients with similar symptoms. Awareness of this difference might allow a more rational approach to treatment. This hypothesis was tested in a small pilot study treating functional dysphagia with cisapride. Three of nine patients had marked symptomatic improvement within 4 weeks and all three had an unresponsive oesophagus. The remaining six patients, who had failure of distal inhibition or a normal response, did not improve.

Topics: Adult; Aged; Catheterization; Cisapride; Deglutition Disorders; Esophageal Diseases; Esophagus; Female; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Peristalsis; Piperidines; Reflex, Abnormal; Serotonin Receptor Agonists