Management Of Visceral Pain Research Articles

Dietary and pharmacological treatment of abdominal pain in IBS.

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-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), μ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)μ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin).

Visceral pain triggered by traction on the ileocecal ligament with ileitis.

BackgroundVisceral pain is a common symptom of several gastrointestinal disorders. Despite tremendous progress in understanding its basic mechanisms, it remains a significant health challenge for clinicians. The present study quantified the intensity of visceral pain using ileocecal ligament traction on an inflamed ileum in goats.Materials and methodsA total of 36 male goats weighing 20.05±2.1 kg were randomly allocated equally into a 2,4,6-trinitrobenzenesulfonic acid (TNBS) group (n=18) and a saline group (n=18). Ileitis was induced via the injection of 30 mg TNBS dissolved in 30% ethanol into the ileal wall through a laparotomy. An equal volume of normal saline was injected into the ileal wall of the saline goats. Behavioral responses to traction (2, 4, and 6 N) on the ileocecal ligament were observed on days 3, 7, and 14. Six goats from each group received a laparotomy and partial intestinal resection for ileal sample collection immediately after behavioral testing on days 3, 7, and 14. Ileal histopathological changes were assessed and concentrations of myeloperoxidase, IL-1β, IL-6, and TNFα investigated using enzyme-linked immunosorbent assay.ResultsThe TNBS-treated goats exhibited remarkably increased macroscopic scores, mast-cell counts, myeloperoxidase, and TNFα concentrations on days 3 and 7 compared to the saline group, and increased microscopic scores and IL-1β and IL-6 concentrations on days 3–14. The TNBS-treated goats exhibited behavioral changes in response to traction in the same pattern as their microscopic changes and cytokine levels. The traction force correlated positively with pain-behavior responses.ConclusionTraction on the ileocecal ligament of goats with ileitis provoked an apparent, stable, and reproducible ileum-derived pain. The current model may be helpful in evaluating the efficacy of new drugs for the management of visceral pain and in investigating its underlying mechanisms.

Preliminary study on attitudes, opinions and knowledge of Italian veterinarians with regard to abdominal visceral pain in dogs

ObjectiveTo determine the attitudes, opinions and knowledge of Italian veterinarians regarding abdominal visceral pain in canine practice. Study designProspective online survey. MethodsAn online questionnaire was created on a Google Form spreadsheet and the weblink was circulated to Italian veterinarians on several mailing lists. The questionnaire, which was available between November 2012 and July 2013, comprised 18 closed, semi-closed and open questions divided into five sections (aetiology, recognition and assessment, drug choices for canine visceral pain, general knowledge about pain management and desire for further education, and demographic information). ResultsA total of 527 responses to the questionnaire were completed. Pancreatitis (19%), gastroenteritis (17%) and gastrointestinal obstructions or foreign bodies (9%) were highlighted as the most frequent causes of abdominal visceral pain. Posture, gait and movement changes (32%) and physiological changes (31%) were commonly quoted for pain recognition and assessment. Most respondents (74%) did not use pain scoring systems. Pancreatitis and peritonitis were considered the most painful abdominal conditions. Opioids (40%), nonsteroidal anti-inflammatory drugs (21%) and tramadol (20%) were cited as drugs for the management of visceral pain. A large percentage of respondents (97%) believed that their knowledge regarding pain management required improvement. There is practitioner interest for more continuing education in the subject. Most respondents were women (66%), aged between 25 and 40 years (57%). Internal medicine (56%), surgery (34%) and anaesthesiology (29%) were the main three speciality areas of interest in this study. Conclusions and clinical relevanceThis online survey represents the opinion of a small number of Italian veterinarians regarding the assessment and treatment of canine abdominal visceral pain. The results show that Italian veterinarians are aware of the main causes and clinical signs of canine visceral pain. Pain-scoring systems are not often used for the recognition and assessment of pain; however, according to these veterinarians, visceral pain is commonly diagnosed.

Management of chronic visceral pain.

Despite marked differences in underlying pathophysiology, the current management of visceral pain largely follows the guidelines derived from the somatic pain literature. The effective management of patients with chronic visceral pain should be multifaceted, including both pharmacological and psychological interventions, thereby providing a mechanism-orientated approach to treatment. Patients can frequently become disenfranchised, and subsequently disengaged, with healthcare providers leading to repeated consultations. Thus, a key aspect of management is to break this cycle by validating patients' symptoms, adopting an empathic approach and taking time to educate patients. To optimize treatment and outcomes in chronic visceral pain we need to move away from approaches exclusively based on dealing with peripheral nociceptive input toward more holistic strategies, taking into account alterations in central pain processing.

Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain.

Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6–S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.

Ellagic acid enhances the antinociceptive action of venlafaxine in mouse acetic acid-induced pain: An isobolographic analysis

BackgroundSeveral antidepressants have been used to treat severe pain in clinics. Recently, it has been shown that ellagic acid (EA), a major constituent of pomegranate juice, produced antinociceptive and anti-inflammatory effect through the central and peripheral sites of action. Materials and methodsIn this study, we examined the interaction between EA and venlafaxine (VLF) on pain induced by intraperitoneal acetic acid in mice using isobolographic analysis. ResultsEA (0.3–10mg/kg, ip) and VLF (3–60mg/kg, ip) produced a dose-dependent inhibition of the writhing response evoked by acetic acid. Fifty percent effective dose (ED50) values against writhing behaviors were 1.02 (0.86–1.19)mg/kg and 12.37 (9.74–15.37)mg/kg for EA and VLF, respectively, and also with higher potency than that of VLF. Co-administration of increasing fractional increments of ED50 doses of EA and VLF produced synergistic interaction against writhing behaviors, as revealed by isobolographic analysis. ConclusionThe synergistic action of EA and VLF provides valuable tool referring to the management of visceral pain.

Safety, Tolerability and Pharmacokinetics of Trimebutine 3-Thiocarbamoylbenzenesulfonate (GIC-1001) in a Randomized Phase I Integrated Design Study: Single and Multiple Ascending Doses and Effect of Food in Healthy Volunteers

PurposeTrimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. MethodsGIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m2. The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. FindingsThe most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, Tmax of trimebutine ranged from 1.0 to 1.5 hours. Cmax and AUCT were linear (nonlinearity P ≥ 0.05) and proportional (P < 0.05) over the studied dose range. Food increased the Cmax and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84–234) and 174% (138–221), respectively. In the MAD study portion, the Tmax of trimebutine ranged from 0.5 to 2 hours and AUCτ increased from 38 to 170 ng · h/mL. AUCτ and Cmax were linear and proportional over the studied dose range. ImplicationsGIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.)

Spinal Cord Stimulation for Visceral Pain—A Novel Approach

Spinal cord stimulation and dorsal column stimulation have been used successfully in the management of visceral pain for many years. A novel technique of ventral column stimulation has been used in our institute with good outcomes since 2007. We describe a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with spinal cord stimulation were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. There was significant reduction in visual analog pain scores from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. There is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multicenter trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies.

Intrathecal tramadol versus intrathecal fentanyl for visceral pain control during bupivacaine subarachnoid block for open appendicectomy

Profound side-effects following intrathecal use of local anesthetics as the sole drugs of choice make spinal anesthesia for open appendicectomy uncommon. The aim of this study was to evaluate the effectiveness of intra-operative analgesia produced by intrathecal tramadol and fentanyl during bupivacaine spinal anesthesia for open appendicectomy. A prospective randomized study was performed. A total of 186 American Society of Anesthesiologists 1 or 11 patients scheduled for emergency open appendicectomy were analyzed. Group FB ( n = 62) received intrathecal fentanyl 25 μg plus 3 ml of 0.5% hyperbaric bupivacaine, Group SB ( n = 62) received 0.5 ml normal saline plus 3 ml of 0.5% hyperbaric bupivacaine and Group TB ( n = 62) received intrathecal tramadol 25 mg plus 3 ml of 0.5% hyperbaric bupivacaine. Visual analog scale scores and frequency of subjective symptoms among patients in the three groups formed the primary outcome measure of this study. Effective intraoperative sensory block was achieved in 100% of patients in group FB and TB while 29 (46.8%) patients in group SB had ineffective sensory block ( P = 0.0001). The pain free period was significantly longer in patients in Group FB than Group SB and TB. Mean time for Group FB with regard to first analgesic request was 304.73 ± 67.91 min, Group SB was 146.59 ± 36.62 and Group TB was 238.39 ± 61.28 min. Incidence of complications were comparable among the three groups. This study showed that intrathecal tramadol (25 mg) can safely replace intrathecal fentanyl (25 μg) in the management of visceral pain and discomfort during subarachnoid block for appendicectomy.

Dor visceral em pós-operatório complicado de cirurgia urológica: relato de caso

JUSTIFICATIVA E OBJETIVOS: Os pacientes que sofrem de dor visceral podem apresentá-la em diferentes áreas do corpo. Este tipo de dor é percebido de forma difusa, diferente da dor por estimulação dolorosa cutânea, no que concerne a localização e intervalo de aparecimento. O objetivo deste estudo foi demonstrar um caso de dor visceral em paciente submetido a procedimento urológico seguido de complicação no pós-operatório RELATO DO CASO: Paciente do gênero masculino, 60 anos, em uso de varfarina, deu entrada no pronto-socorro apresentando quadro de dor abdominal com predominância em flanco esquerdo, 48 horas após procedimento urológico transuretral. Na investigação complementar foi identificada a presença de hematoma retroperitonial em loja renal esquerda. Inicialmente o paciente recebeu tratamento conservador, e foi iniciada analgesia com morfina por via endovenosa através de bomba de analgesia controlada pelo paciente. Com o aumento do hematoma, optou-se por intervenção cirúrgica para realização de nefrectomia esquerda. CONCLUSÃO: A convergência neurofisiológica dos aferentes somáticos e viscerais que adentram o sistema nervoso central parece explicar a dor visceral referida, onde estímulos nóxicos sobre as vísceras provocam dor referida em áreas somáticas. Este caso ilustra o manuseio de um caso de dor visceral aguda onde a utilização de analgesia venosa controlada por paciente com morfina associada à dipirona foi empregada como estratégia para o controle de dor, para o qual se mostrou eficiente.

Visceral pain readouts in experimental medicine

Visceral pain is studied at the level of the primary afferent fiber, spinal cord, subcortical, and cortical levels electrophysiologically and using brain imaging, which provides an objective measure of excitation at each level. However, correlation of these with actual perception of pain in conscious animal models has been problematic, and we rely on indirect measures in most preclinical research. The main method is electromyographic recording of abdominal muscle contractions in response to colorectal distension (CRD), which may reflect reflexes set up at several levels of the above pathway. Several experimental treatments for visceral pain have failed in clinical trials, possibly because of failure to translate from preclinical observations on CRD responses in animals to perception of spontaneous events in patients. Therefore, we need more objective outcomes. In this NGM issue, Hultin et al. show feasibility of routine recordings of cortical evoked electrical potentials (CEP) using implanted cranial electrodes in response to graded CRD in rats. CEP comprised three temporal components with latencies of approximately 20-50 ms, 90-180 ms, and 300 ms, which were reproducible and graded in intensity and latency with distension pressure. From this basic study it is clear that colorectal evoked potentials can be recorded reliably in awake rats and may serve as an objective marker for centrally projecting visceral sensory signals in rodents. It remains to be seen how these responses are affected by drugs under development for clinical management of visceral pain, and if there is improved translation.

Drug management of visceral pain: concepts from basic research.

Visceral pain is experienced by 40% of the population, and 28% of cancer patients suffer from pain arising from intra- abdominal metastasis or from treatment. Neuroanatomy of visceral nociception and neurotransmitters, receptors, and ion channels that modulate visceral pain are qualitatively or quantitatively different from those that modulate somatic and neuropathic pain. Visceral pain should be recognized as distinct pain phenotype. TRPV1, Na 1.8, and ASIC3 ion channels and peripheral kappa opioid receptors are important mediators of visceral pain. Mu agonists, gabapentinoids, and GABAB agonists reduce pain by binding to central receptors and channels. Combinations of analgesics and adjuvants in animal models have supra-additive antinociception and should be considered in clinical trials. This paper will discuss the neuroanatomy, receptors, ion channels, and neurotransmitters important to visceral pain and provide a basic science rationale for analgesic trials and management.

GLT‐1 over‐expression mitigates chronic bladder inflammation and GLuR1 trafficking

Strategies to attenuate glutamate induced changes in synaptic activity may lead to better options in visceral pain management. Previous data in our laboratory showed that animals over‐expressing the glutamate transporter GLT‐1, crucial for glutamate removal, had a visceromotor response (VMR) to urinary bladder distension (UBD) that was inhibited 57–64%. The current study showed that intrathecal pretreatment with dihydrokainate (DHK; 0.03mM), a selective GLT‐1 blocker, reversed this response and intracisternal administration of DHK was not effective. Also, a chronic bladder inflammation model was established via intraperitoneal treatment of cyclophosphamide (80mg/kg; day 0, 2, 4, and 6) and measured the VMR associated with urinary bladder distension in mice. The data showed that cyclophosphamide treatment significantly increased VMR (66%–120% at 0.15 and 0.2mL) and the effect was diminished by GLT‐1 over‐expression. To study trafficking of the GLuR1 subunit from the cytosol to the membrane in the lumbosacral spinal region of animals with chronic bladder inflammation, cyclophosphamide was administered as previously described, and the results showed a 33% increase in total GluR1 and a 27% increase in membrane GLuR1 compared to controls. A small increase was recorded in the cytosol (&lt;10%). GLT‐1 over‐expression attenuated the increased total (9%) and membrane (11%) GLuR1expression. Overall, this study suggests that GLT‐1 over‐expression mitigates visceral nociception due to chronic bladder inflammation and trafficking of GLuR1 to the membrane may be involved. Supported by NIH DK 071839 (RLS) and APS Porter Fellowship (KR).

An atypical case of nephrolithiasis with transient remission of symptoms following spinal manipulation

Objective Nephrolithiasis is a common condition with symptoms similar to common mechanical lesions of the lumbar spine and pelvis. The purpose of this report is to outline a case of nephrolithiasis that closely mimicked sacroiliac joint syndrome in subjective report, objective findings, and reduction of symptoms with spinal manipulation. Clinical Features A 41-year-old obese male patient with mild pain over the left posterior sacroiliac joint, penile paresthesia, and the penile sensation of urinary urgency presented for chiropractic care. Subjective history and objective evaluation suggested sacroiliac joint syndrome. Intervention and Outcome A trial of conservative management including spinal manipulation was initiated. Following each treatment, the patient reported temporary relief of all symptoms (4 hours to 2 days). After unsuccessful permanent resolution of symptoms, a urinalysis was performed; and a follow-up computerized tomography scan revealed a large renal calculus obstructing the left ureter. Laser lithotripsy produced obliteration of the stone and complete resolution of symptoms. Conclusions This report outlines the potential overlap of symptoms of visceral and somatic lesions in both presentation and response to care. In this case, a favorable response to spinal manipulation masked the most likely underlying symptom generator. This encounter demonstrates the potential need for further clinical examination in the instance of the unresponsive mechanical lesion. This report also supports the need for future research into spinal manipulation as a possible adjunct for visceral pain management.

Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service

ObjectiveThis study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain.MethodA retrospective, observational...

Analgesic Efficacy of Peripheral κ-Opioid Receptor Agonist CR665 Compared to Oxycodone in a Multi-modal, Multi-tissue Experimental Human Pain Model

Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Inside Information: The Unique Features of Visceral Sensation

Most of what is written and believed about pain and nociceptors originates from studies of the "somatic" (non-visceral) sensory system. As a result, the unique features of visceral pain are often overlooked. In the clinic, the management of visceral pain is typically poor, and drugs that are used with some efficacy to treat somatic pain often present unwanted effects on the viscera. For these reasons, a better understanding of visceral sensory neurons-particularly visceral nociceptors-is required. This review provides evidence of functional, morphological, and biochemical differences between visceral and non-visceral afferents, with a focus on potential nociceptive roles, and also considers some of the potential mechanisms of visceral mechanosensation.

Effects of General Anesthetics on Visceral Pain Transmission in the Spinal Cord

Current evidence suggests an analgesic role for the spinal cord action of general anesthetics; however, the cellular population and intracellular mechanisms underlying anti-visceral pain by general anesthetics still remain unclear. It is known that visceral nociceptive signals are transmited via post-synaptic dorsal column (PSDC) and spinothalamic tract (STT) neuronal pathways and that the PSDC pathway plays a major role in visceral nociception. Animal studies report that persistent changes including nociception-associated molecular expression (e.g. neurokinin-1 (NK-1) receptors) and activation of signal transduction cascades (such as the protein kinase A [PKA]-c-AMP-responsive element binding [CREB] cascade)-in spinal PSDC neurons are observed following visceral pain stimulation. The clinical practice of interruption of the spinal PSDC pathway in patients with cancer pain further supports a role of this group of neurons in the development and maintenance of visceral pain. We propose the hypothesis that general anesthetics might affect critical molecular targets such as NK-1 and glutamate receptors, as well as intracellular signaling by CaM kinase II, protein kinase C (PKC), PKA, and MAP kinase cascades in PSDC neurons, which contribute to the neurotransmission of visceral pain signaling. This would help elucidate the mechanism of antivisceral nociception by general anesthetics at the cellular and molecular levels and aid in development of novel therapeutic strategies to improve clinical management of visceral pain.

Gabapentin action and interaction on the antinociceptive effect of morphine on visceral pain in mice

Visceral pain is one of the most common forms of pain and for which new drugs would be welcome. The aim of this study was to investigate whether gabapentin inhibits induced abdominal contractions in mice and to examine the effect of its co-administration with morphine. A total of 96 mice received acetic acid intraperitoneally after administration of saline or gabapentin (1, 5, 10, 50 and 100 mg kg(-1)) or morphine (0.25, 0.5, 1, 3 and 5 mg kg(-1)) or a combination of morphine and gabapentin. Other groups also received naloxone. The number of writhes were counted. Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes was decreased significantly by gabapentin (50 and 100 mg kg(-1)) and morphine (0.5, 1, 3 and 5 mg kg(-1)) (P < 0.001). Also, the lowest dose of morphine 0.25 mg kg(-1) when combined with low doses of gabapentin significantly decreased the number of writhes (P < 0.005). The combination of a low effective dose of gabapentin (50 mg kg(-1)) with a low dose of morphine decreased the writhing by 94% as compared to the controls. The antinociceptive effect of combined administration was not reversed by naloxone. These data demonstrated the comparable efficacy of gabapentin with morphine in visceral pain. Also, the results showed that the combination of doses of gabapentin and morphine, which were ineffective alone, produced a significant analgesic effect in the writhing model of pain. This may be clinically important in the management of visceral pain.

Intrathecal gabapentin enhances the analgesic effects of subtherapeutic dose morphine in a rat experimental pancreatitis model.

Morphine sulfate has long been used for analgesia, but clinical applications can be limited by side effects, tolerance, and potential for addiction at therapeutic doses. An agent that produces therapeutic analgesia when coadministered with low-dose morphine could have important clinical uses. The anticonvulsant agent gabapentin has been identified as having antihyperalgesic properties acting on the alpha2delta1 subunit of N-type voltage-activated calcium channels on dorsal root ganglia neurons. In this study, intrathecal gabapentin, which by itself is ineffective when administered spinally, was combined with low-dose morphine and tested in an acute bradykinin-induced pancreatitis model in rats. An intrathecal catheter was surgically inserted into the subarachnoid space of male Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid, gabapentin, morphine, or combined gabapentin and morphine 30 min before bradykinin injection into the bile-pancreatic duct. Spontaneous behavioral activity (cage crossing, rearing, and hind limb extension) was monitored before drug injection (baseline) and after bradykinin injection into the bile-pancreatic duct to assess visceral pain. Spinal pretreatment with up to 300 microg gabapentin alone was not effective in reducing hind limb extension in this model, but did restore some cage crossing and rearing behaviors. Spinal treatment with low-dose morphine reduced hind limb extension only. Spinal pretreatment with combined gabapentin and subtherapeutic doses of morphine sulfate resulted in restoration of all spontaneous behaviors to surgical baseline levels including elimination of hind limb extension. Combined spinal administration of gabapentin and low doses of morphine significantly reduces pain-related behaviors in this acute rat pancreatitis model, whereas these agents were ineffective when used alone in this dose range. These data suggest that the alpha2delta1 subunit of the N-type voltage-activated Ca2+ channels is involved in transmission of this visceral pain, likely through effects on primary afferent endings in the spinal cord. Thus, gabapentin may be an effective adjuvant to initial low dose spinal opioid therapy for clinical management of visceral pain.