piperidines and Visceral-Pain

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT

Topics: Abdominal Pain; Anti-Infective Agents; Antidepressive Agents; Butyrophenones; Dipeptides; GABA Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Imidazoles; Irritable Bowel Syndrome; Mentha piperita; Parasympatholytics; Phenylalanine; Piperidines; Plant Oils; Probiotics; Quaternary Ammonium Compounds; Rifamycins; Rifaximin; Serotonin 5-HT3 Receptor Antagonists; Thiophenes; Visceral Pain

Umbilical artery serum-derived exosomes (UEs) serve as messengers for maternal-fetal information exchange and cellular regulation. Intravenous remifentanil could be considered as an effective adjunct to epidural anesthesia in providing a favorable analgesia effect for cesarean section (C-section), but its effects on UEs are currently unknown.. From 01/12/2021 to 30/06/2022, eligible parturients scheduled for repeated C-section at the First Affiliated Hospital of Wenzhou Medical University were randomized to receive either an intravenous bolus (0.15 μg/kg) followed by a continuous infusion (0.075 μg/kg/min) of remifentanil or normal saline throughout the procedure. The primary outcome was the number of UEs. Secondary outcomes included the size and protein amount of UEs, the vital signs, visceral pain score, sedation score, maternal satisfaction score, Apgar score, the incidence of neonatal asphyxia, umbilical arterial pH, and the presence of complications.. Nanoparticle tracking analysis indicated similar size of UEs between the two groups, but the number and protein amount of UEs were increased in the remifentanil group  compared to the control group (P < 0.05). In parturients receiving remifentanil, visceral pain scores were decreased, which was accompanied by the increased scores of maternal satisfaction with the anesthetic method (P < 0.05). Other maternal and neonatal outcomes were comparable between the two groups (P > 0.05).. The intravenous administration of remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia, with improved birth experience and minimal neonatal complications.

Topics: Analgesics, Opioid; Anesthesia, Epidural; Cesarean Section; Exosomes; Female; Humans; Infant, Newborn; Infusions, Intravenous; Piperidines; Pregnancy; Remifentanil; Umbilical Arteries; Visceral Pain

The use of epidural ropivacaine may result in significant haemodynamic fluctuations during combined epidural and general anaesthesia. We designed this study to investigate whether epidural anaesthesia with a goal-directed approach, when combined with general anaesthesia, improved haemodynamic stability in elderly patients undergoing major abdominal surgery. Seventy-five elderly patients undergoing major abdominal surgery were randomly and evenly assigned to one of three groups receiving intraoperative epidural anaesthesia with either ropivacaine 0.1% (Group 1), ropivacaine 0.375% (Group 2) or ropivacaine 0.375% for abdominal wall pain and ropivacaine 0.1% for visceral pain (Group 3). General anaesthesia was induced using a target-controlled infusion of combined propofol and remifentanil. The remifentanil target concentration was adjusted according to the mean arterial pressure and heart rate, and vasoactive agents were administered to maintain stable haemodynamics. The need for vasoactive drug administrations was 1.4 (standard deviation 0.9) in Group 3 (n=24), representing a significantly lower frequency of administration compared with Groups 1 (n=24) and 2 (n=24) (P <0.05 versus Group 1; P <0.01 versus Group 2). The total intraoperative dose of remifentanil was significantly greater in Group 1 (P <0.01 versus Group 2; P <0.05 versus Group 3) but did not differ significantly between Groups 2 and 3. Goal-directed epidural anaesthesia with different ropivacaine concentrations can improve haemodynamic stability when combined with general anaesthesia for elderly patients undergoing major abdominal surgery.

Topics: Abdomen; Age Factors; Aged; Amides; Anesthesia, Epidural; Anesthesia, General; Anesthetics, Local; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Heart Rate; Humans; Male; Pain; Piperidines; Propofol; Remifentanil; Ropivacaine; Visceral Pain

Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS.. To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not.. Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed.. Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus).. Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Anxiety; Arousal; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Emotions; Female; Humans; Irritable Bowel Syndrome; Middle Aged; Neurokinin-1 Receptor Antagonists; Pain; Pain Measurement; Pain Threshold; Pilot Projects; Piperidines; Receptors, Neurokinin-1; Stress, Psychological; Visceral Pain; Young Adult

Irritable bowel syndrome (IBS) is one of the most common challenging diseases for clinical treatment. The aim of this study is to investigate whether transcranial direct current stimulation (tDCS) has analgesic effect on visceral hypersensitivity (VH) in an animal model of IBS as well as the underlying mechanism. As the activation of GluN2B in anterior cingulate cortex (ACC) takes part in VH, we examined whether and how GluN2B in ACC takes part in the effect of tDCS. Neonatal maternal deprivation (NMD), a valuable experimental model to study the IBS pathophysiology, was used to induce visceral hypersensitivity of rats. We quantified VH as colorectal distention threshold and performed patch-clamp recordings of ACC neurons. The expression of GluN2B were determined by RT-qPCR and Western blotting. The GluN2B antagonist Ro 25-6981 was microinjected into the rostral and caudal ACC. tDCS was performed for 7 consecutive days. It was found that NMD decreased expression of GluN2B, which could be obviously reversed by tDCS. Injection of Ro 25-6981 into rostral and caudal ACC of normal rats induced VH and also reversed the analgesic effect of tDCS. Our data sheds light on the nonpharmacological therapy for chronic VH in pathological states such as IBS.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gyrus Cinguli; Hyperalgesia; Irritable Bowel Syndrome; Male; Patch-Clamp Techniques; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Transcranial Direct Current Stimulation; Visceral Pain

Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid-induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Avoidance Learning; Behavior, Animal; Ketoprofen; Male; Mice; Mice, Inbred ICR; Morphine; Piperidines; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tetrahydroisoquinolines; Visceral Pain

We previously reported estrogen modulates spinal N-methyl-d-aspartate (NMDA) receptor processing of colorectal pain through changes in spinal GluN1 subunit phosphorylation/expression. The purpose of this study was to investigate whether spinal GluN2B containing NMDA receptors are involved in estrogen modulation of visceral pain processing.. Behavioral, molecular, and immunocytochemical techniques were used to determine spinal GluN2B expression/phosphorylation and function 48 h following subcutaneous injection of estradiol (E2) or vehicle (safflower oil, Saff oil) in ovariectomized rats in the absence or presence of colonic inflammation induced by mustard oil.. E2 increased the magnitude of the visceromotor response (VMR) to colorectal distention compared to Saff oil in non-inflamed rats. Intrathecal injection of the GluN2B subunit antagonist, Ro 25-6981, had no effect on the VMR in non-inflamed E2 or Saff oil rats. Colonic inflammation induced visceral hyperalgesia in E2, but not Saff oil rats. Visceral hyperalgesia in E2 rats was blocked by intrathecal GluN2B subunit selective antagonists. In inflamed rats, E2 increased GluN2B protein and gene expression in the thoracolumbar (TL), but not lumbosacral (LS), dorsal spinal cord. Immunocytochemical labeling showed a significant increase in GluN2B subunit in the superficial dorsal horn of E2 rats compared to Saff oil rats.. These data support the hypothesis that estrogen increases spinal processing of colonic inflammation-induced visceral hyperalgesia by increasing NMDA receptor activity. Specifically, an increase in the activity of GluN2B containing NMDA receptors in the TL spinal cord by estrogen underlies visceral hypersensitivity in the presence of colonic inflammation.

Topics: Animals; Behavior, Animal; Colitis; Estradiol; Estrogens; Female; Hyperalgesia; Immunohistochemistry; Lumbar Vertebrae; Mustard Plant; Ovariectomy; Phenols; Phosphorylation; Piperidines; Plant Oils; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Thoracic Vertebrae; Visceral Pain

Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models.. Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing.. PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR).. The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain.

Topics: Amidohydrolases; Animals; Benzodioxoles; Carbamates; Colon; Cyclohexanols; Inflammation; Male; Mice; Mice, Inbred BALB C; Monoacylglycerol Lipases; Pain Measurement; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Visceral Pain

Cholecystokinin (CCK), a gut hormone that is released during feeding, exerts gastrointestinal effects in part through vagal pathway. It is reported to be a potential trigger for increased postprandial visceral sensitivity in healthy subjects and, especially in patients with irritable bowel syndrome. NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the central amygdala (CeA) participate in pain modulation. Systemically administered CCK activates the CeA-innervating neurons. Here, we investigated whether CCK modulation of visceral sensitivity is mediated through CeA NMDA-NR2B receptors and whether this modulation involves vagal pathway.. We first examined the visceromotor response (VMR) to colorectal distention (CRD) following i.p. injection of CCK octapeptide (CCK-8) in a rat model. Next, the NR2B antagonist ifenprodil and the NR2A antagonist NVP-AAM077 were microinjected into the CeA before systemic CCK injection. NR2B phosphorylation was detected by Western blot. To down-regulate NR2B gene expression, NR2B-specific small interfering RNA (siRNA) was delivered into CeA neurons by electroporation. In addition, the effects of functional deafferentation by perivagal application of capsaicin and pretreatment with the CCK1 receptor antagonist devazepide were investigated.. CCK-8 increased VMR to CRD in a dose-dependent manner. This effect was blunted by intra-CeA administration of ifenprodil (but not NVP-AAM077) and was accompanied by phosphorylation of NR2B subunits in the CeA. CCK failed to increase VMR to CRD in NR2B siRNA-treated rats. Perivagal capsaicin application and pretreatment with devazepide prevented CCK-induced pronociception and CeA NR2B phosphorylation.. The pronociception induced by systemic CCK, which is vagal afferent-dependent, requires activation of CeA NMDA-NR2B receptors.

Topics: Abdominal Muscles; Afferent Pathways; Animals; Central Amygdaloid Nucleus; Hyperalgesia; Male; Nociception; Pain Measurement; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sincalide; Vagotomy; Vagus Nerve; Visceral Pain

The roles of spinal N-methyl-d-aspartic acid receptor 2B (NR2B) subunit in central sensitization of chronic visceral pain were investigated. A rat model with irritable bowel syndrome (IBS) was established by colorectal distention (CRD) on post-natal days 8-14. Responses of the external oblique muscle of the abdomen to CRD were measured to evaluate the sensitivity of visceral pain in rats. The sensitivity of visceral pain significantly increased in IBS-like rats. Expressions of spinal NR2B subunit and phosphorylated NR2B subunit significantly increased by 50-55% in IBS-like rats when compared with those in control rats. Ro 25-6981, a selective antagonist of NR2B subunit, has a dose-dependent anti-allodynic and anti-hyperalgesic effect without causing motor dysfunction in IBS-like rats. Furthermore, the activation mechanism of the spinal NR2B subunit in chronic visceral pain was also investigated. Spinal administration of genistein, a specific inhibitor of tyrosine kinases, also decreased the visceral pain hypersensitivity of IBS-like rats in a dose-dependent manner. In addition, the expression of phosphorylated NR2B subunit was decreased after spinal administration of Ro 25-6981 or genistein in IBS-like rats. In conclusion, tyrosine kinase activation-induced phosphorylation of NR2B subunit may play a crucial role in central sensitization of chronic visceral pain.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Excitatory Amino Acid Antagonists; Genistein; Irritable Bowel Syndrome; Male; Pain Measurement; Phenols; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Time Factors; Tyrosine; Visceral Pain

Acute and chronic pain resulting from injury, surgery, or disease afflicts >100 million Americans each year, having a severe impact on mood, mental health, and quality of life. The lack of structural and functional information for most ion channels, many of which play key roles in the detection and transmission of noxious stimuli, means that there remain unidentified therapeutic targets for pain management. This study focuses on the transient receptor potential canonical subfamily 4 (TRPC4) ion channel, which is involved in the tissue-specific and stimulus-dependent regulation of intracellular Ca²⁺ signaling. Rats with a transposon-mediated TRPC4-knockout mutation displayed tolerance to visceral pain induced by colonic mustard oil (MO) exposure, but not somatic or neuropathic pain stimuli. Moreover, wild-type rats treated with a selective TRPC4 antagonist (ML-204) prior to MO exposure mimicked the behavioral responses observed in TRPC4-knockout rats. Significantly, ML-204 inhibited visceral pain-related behavior in a dose-dependent manner without noticeable adverse effects. These data provide evidence that TRPC4 is required for detection and/or transmission of colonic MO visceral pain sensation. In the future, inhibitors of TRPC4 signaling may provide a highly promising path for the development of first-in-class therapeutics for this visceral pain, which may have fewer side effects and less addictive potential than opioid derivatives.

Topics: Analgesics; Animals; Colon; Dose-Response Relationship, Drug; Female; Gene Knockout Techniques; Indoles; Male; Mustard Plant; Neuralgia; Nociception; Nociceptive Pain; Piperidines; Plant Oils; Rats; Rats, Inbred F344; Rats, Transgenic; RNA, Messenger; TRPC Cation Channels; Visceral Pain

Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2-arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.

Topics: Adult; Animals; Arachidonic Acids; Cannabinoid Receptor Antagonists; Endocannabinoids; Female; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Male; Middle Aged; Nociception; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Serotonin; Vagus Nerve; Visceral Pain

Pain and learning memory have striking similarities in synaptic plasticity. Activation of the N-methyl-D-aspartic acid receptors 2B subunits (NR2B-NMDAs) is responsible for the hippocampal LTP in memory formation. In our previous studies, we found the significant enhancement of CA1 hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in rats with chronic visceral pain. However, it is unclear whether the NR2B-NMDAs are required for the LTP in chronic visceral pain. In this study, a rat model with irritable bowel syndrome (IBS) was established by colorectal distention (CRD). The sensitivity of visceral pain and HFS-induced LTP at SC-CA1 synapses were significantly enhanced in IBS-like rats (p<0.05). In addition, hippocampal NR2B protein levels significantly increased in IBS-like rats (p<0.05). To test whether NR2B-NMDAs are responsible for the LTP, effects of Ro 25-6981, a selective antagonist of NR2B-NMDAs, on field potential in CA1 region were investigated in vitro. Our results demonstrated that Ro 25-6981 dose-dependently inhibited the facilitation of CA1 LTP in IBS-like rats. The plausible activation mechanism of hippocampal NR2B-NMDAs in the LTP enhancement was further explored. Western blot data indicated that expression of tyrosine phosphorylated NR2B protein in hippocampus significantly enhanced in IBS-like rats. Accordingly, genistein, a specific inhibitor of tyrosine kinases, dose-dependently blocked the facilitation of hippocampal LTP in IBS-like rats. Furthermore, EMG data revealed that intra-hippocampal injection of Ro 25-6981 dose-dependently attenuated the visceral hypersensitivity. In conclusion, hippocampal NR2B-NMDAs are responsible for the facilitation of CA1 LTP via tyrosine phosphorylation, which leads to visceral hypersensitivity.

Topics: Animals; CA1 Region, Hippocampal; Chronic Pain; Disease Models, Animal; Excitatory Amino Acid Antagonists; Genistein; Hippocampus; Hyperalgesia; Irritable Bowel Syndrome; Long-Term Potentiation; Male; Phenols; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses; Visceral Pain

Cannabis is widely used for treating a number of gastrointestinal ailments, but its use is associated with several adverse effects, particularly when the route of administration is via smoking. In the present study, we tested the effects (in rats) of a simple extract of medicinal cannabis (called "MFF") for its ability to promote resolution of colitis, to prevent gastric damage induced by naproxen, and to reduce gastric distention-induced visceral pain. Intracolonic, but not oral administration of MFF dose-dependently reduced the severity of hapten-induced colitis, an effect not reduced by pretreatment with antagonists of CB1 or CB2 receptors. Significant improvement of symptoms (diarrhea, weight loss) and healing of ulcerated tissue was evident with MFF treatment at doses that did not produce detectable urinary levels of 9-Δ-tetrahydrocannabinol (THC). MFF increased colonic hydrogen sulfide synthesis in healthy rats, but not in rats with colitis, and had no effect on colonic prostaglandin E2 synthesis. Orally, but not systemically administered MFF dose-dependently reduced the severity of naproxen-induced gastric damage, and a CB1 antagonist reversed this effect. MFF prevented gastric distention-induced visceral pain via a CB2-dependent mechanism. These results demonstrate that a simple extract of medicinal cannabis can significantly enhance resolution of inflammation and injury, as well as prevent injury, in the gastrointestinal tract. Interestingly, different cannabinoid receptors were involved in some of the effects. MFF may serve as the basis for a simple preparation of cannabis that would produce beneficial effects in the GI tract with reduced systemic toxicity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cannabis; Colitis; Gastrointestinal Tract; Hydrogen Sulfide; Indoles; Male; Naproxen; Piperidines; Plant Extracts; Protective Agents; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Stomach Ulcer; Visceral Pain

Although electroencephalographic parameters and auditory evoked potentials (AEP) reflect the hypnotic component of anesthesia, there is currently no specific and mechanism-based monitoring tool for anesthesia-induced blockade of nociceptive inputs. The aim of this study was to assess visceral pain-evoked potentials (VPEP) and contact heat-evoked potentials (CHEP) as electroencephalographic indicators of drug-induced changes of visceral and somatosensory pain. Additionally, AEP and electroencephalographic permutation entropy were used to evaluate sedative components of the applied drugs.. In a study enrolling 60 volunteers, VPEP, CHEP (amplitude N2-P1), and AEP (latency Nb, amplitude Pa-Nb) were recorded without drug application and at two subanesthetic concentration levels of propofol, sevoflurane, remifentanil, or (s)-ketamine. Drug-induced changes of evoked potentials were analyzed. VPEP were generated by electric stimuli using bipolar electrodes positioned in the distal esophagus. For CHEP, heat pulses were given to the medial aspect of the right forearm using a CHEP stimulator. In addition to AEP, electroencephalographic permutation entropy was used to indicate level of sedation.. With increasing concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine, VPEP and CHEP N2-P1 amplitudes decreased. AEP and electroencephalographic permutation entropy showed neither clinically relevant nor statistically significant suppression of cortical activity during drug application.. Decreasing VPEP and CHEP amplitudes under subanesthetic concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine indicate suppressive drug effects. These effects seem to be specific for analgesia.

Topics: Adult; Analgesics, Opioid; Anesthetics, Dissociative; Anesthetics, Inhalation; Anesthetics, Intravenous; Electric Stimulation; Electroencephalography; Entropy; Evoked Potentials; Evoked Potentials, Auditory; Evoked Potentials, Somatosensory; Humans; Ketamine; Male; Methyl Ethers; Pain; Piperidines; Propofol; Remifentanil; Sevoflurane; Visceral Pain