Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system.

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

The influence of distal colon irritation on the changes of cystometry parameters to esophagus and colon distentions.

The co-occurrence of multiple pathologies in the pelvic viscera in the same patient, such as, irritable bowel syndrome and interstitial cystitis, indicates the complexity of viscero-visceral interactions and the necessity to study these interactions under multiple pathological conditions. In the present study, the effect of distal colon irritation (DCI) on the urinary bladder interaction with distal esophagus distention (DED), distal colon distention (DCD), and electrical stimulation of the abdominal branches of vagus nerve (abd-vagus) were investigated using cystometry parameters. The DCI significantly decreased the intercontraction time (ICT) by decreasing the storage time (ST); nonetheless, DED and Abd-vagus were still able to significantly decrease the ICT and ST following DCI. However, DCD had no effect on ICT following the DCI. The DCI, also, significantly decreased the Intravesical pressure amplitude (P-amplitude) by increasing the resting pressure (RP). Although DED has no effect on the P-amplitude, both in the intact and the irritated animals, the abd-vagus significantly increased the P-amplitude following DCI by increasing the maximum pressure (MP). In the contrary, 3mL DCD significantly increased the P-amplitude by increasing the MP and lost that effect following the DCI. Concerning the pressure threshold (PT), none of the stimuli had any significant changes in the intact animals. However, DCI significantly decreased the PT, also, the abd-vagus and 3mL DCD significantly decreased the PT. The results of this study indicate that chemical irritation of colon complicates the effects of mechanical irritation of esophagus and colon on urinary bladder function.

The influence of distal colon irritation on the changes of cystometry parameters to esophagus and colon distentions

ABSTRACT The co-occurrence of multiple pathologies in the pelvic viscera in the same patient, such as, irritable bowel syndrome and interstitial cystitis, indicates the complexity of viscero-visceral interactions and the necessity to study these interactions under multiple pathological conditions. In the present study, the effect of distal colon irritation (DCI) on the urinary bladder interaction with distal esophagus distention (DED), distal colon distention (DCD), and electrical stimulation of the abdominal branches of vagus nerve (abd-vagus) were investigated using cystometry parameters. The DCI significantly decreased the intercontraction time (ICT) by decreasing the storage time (ST); nonetheless, DED and Abd-vagus were still able to significantly decrease the ICT and ST following DCI. However, DCD had no effect on ICT following the DCI. The DCI, also, significantly decreased the Intravesical pressure amplitude (P-amplitude) by increasing the resting pressure (RP). Although DED has no effect on the P-amplitude, both in the intact and the irritated animals, the abd-vagus significantly increased the P-amplitude following DCI by increasing the maximum pressure (MP). In the contrary, 3mL DCD significantly increased the P-amplitude by increasing the MP and lost that effect following the DCI. Concerning the pressure threshold (PT), none of the stimuli had any significant changes in the intact animals. However, DCI significantly decreased the PT, also, the abd-vagus and 3mL DCD significantly decreased the PT. The results of this study indicate that chemical irritation of colon complicates the effects of mechanical irritation of esophagus and colon on urinary bladder function.

Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling.

BACKGROUND: Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis. METHODS: Trinitrobenzene sulfonic acid (TNBS)-colitis was monitored individually by colonoscopy to confirm colitis and follow convalescence and endoscopic healing in each rat. Experiments were performed in controls, rats with acute colitis and in postcolitis rats. Colonic afferent mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs), and by making extracellular afferent recordings from splanchnic nerve bundles in vitro. Multiunit afferent activity was classified into single units identified as low threshold (LT), wide dynamic range (WDR), high threshold (HT), and mechanically insensitive afferents (MIA). KEY RESULTS: During acute TNBS-colitis, VMRs were significantly increased and splanchnic nerve recordings showed proportionally less MIA and increased WDR and HT afferents. Acute colitis gave rise to an enhanced spontaneous activity of both LT and MIA and augmented afferent mechanosensitivity in LT, WDR and HT afferents. Postcolitis, VMRs remained significantly increased, whereas splanchnic nerve recordings showed that the proportion of LT, WDR, HT and MIA had normalized to control values. However, LT and MIA continued to show increased spontaneous activity and WDR and HT remained sensitized to colorectal distension. CONCLUSIONS & INFERENCES: Visceral hypersensitivity in vivo is associated with sensitized splanchnic afferent responses both during acute colitis and in the postinflammatory phase. However, splanchnic afferent subpopulations are affected differentially at both time points.

Functional and morphological alterations induced by Helicobacter pylori infection in gastric nerve supply.

Helicobacterpylori (HP) infection is the most common cause of many gastric diseases. One of its pathogenic mechanisms involves the production of a wide spectrum of alterations in different components of the gastric enteric nervous system. Changes in neural circuitry encompass structural abnormalities, sensitive and motor function impairment, altered content and release of neurotransmitters, and seem to be related rather to the inflammatory response of gastric wall than to the bacterial colonization. Although gathered data provide new insights into the complex mechanisms underlying the interactions between HP and enteric nervous system, there still are some controversial aspects. Interestingly, it has been suggested that impaired neural activity might have a potential role in gastric carcinogenesis, but this hypothesis requires further investigation. Future studies shall, therefore, elucidate the neuromodulatory influences of Helicobacter pylori infection on the enteric nervous system. A better comprehension on neural changes during HP-induced inflammation could help in identifying new therapeutic options.

Genetic control of the segregation of pain-related sensory neurons innervating the cutaneous versus deep tissues.

Mammalian pain-related sensory neurons are derived from TrkA lineage neurons located in the dorsal root ganglion. These neurons project to peripheral targets throughout the body, which can be divided into superficial and deep tissues. Here, we find that the transcription factor Runx1 is required for the development of many epidermis-projecting TrkA lineage neurons. Accordingly, knockout of Runx1 leads to the selective loss of sensory innervation to the epidermis, whereas deep tissue innervation and two types of deep tissue pain are unaffected. Within these cutaneous neurons, Runx1 suppresses a large molecular program normally associated with sensory neurons that innervate deep tissues, such as muscle and visceral organs. Ectopic expression of Runx1 in these deep sensory neurons causes a loss of this molecular program and marked deficits in deep tissue pain. Thus, this study provides insight into a genetic program controlling the segregation of cutaneous versus deep tissue pain pathways.

VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity.

BACKGROUND: This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity.In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) and cholinergic nerves (ChAT) was studied one week after one or two intravesical instillations of the growth factor.To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG) neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments. RESULTS: In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment) reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation) caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na(+) channels (VGSC) in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation. CONCLUSIONS: For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a key modulator of neural plasticity in the pelvis and enhanced VEGF content may be associated with visceral hyperalgesia, abdominal discomfort, and/or pelvic pain.

Visceral hypersensitivity in endometriosis: a new target for treatment?

OBJECTIVE: In women presenting to gynaecological clinics with lower abdominal pain, the cause is frequently attributed to endometriosis irrespective of whether it is found to be minimal or extensive at laparoscopy. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. METHODS: Visceral sensitivity to balloon distension, symptoms and psychological status were assessed following laparoscopy in 20 women with minimal to mild endometriosis, 20 with moderate to severe endometriosis, 20 with laparoscopy negative abdominal pain and 20 asymptomatic women undergoing laparoscopic sterilisation who acted as controls, and compared with 20 women with IBS. RESULTS: Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p<0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. Patients with laparoscopy negative pain had symptoms and visceral sensitivity similar to patients with IBS. Controls undergoing laparoscopy had normal sensitivity, indicating that the laparoscopic procedure was not inducing hypersensitivity. CONCLUSION: Visceral hypersensitivity is extremely common in endometriosis and could be intensifying the pain. This finding might explain why mildly affected individuals often complain of severe symptoms out of proportion to the extent of their disease. This study has introduced a completely new concept into the understanding of pain in endometriosis and could open up new opportunities for treatment.

Further validation of a model of fibromyalgia syndrome in the rat.

UNLABELLED: We have recently developed an animal model of fibromyalgia syndrome in the rat. In this model, rats exposed to unpredictable sound stress develop a delayed onset enhancement and prolongation of cytokine-induced mechanical hyperalgesia in muscle and skin. In this study, we tested the hypothesis that our model also manifests symptoms of common comorbid diagnoses: irritable bowel syndrome, temporomandibular disorder, and anxiety. Both visceral sensitivity and cytokine hyperalgesia in masseter muscle were present in the stressed rats. Furthermore, in an established model of irritable bowel syndrome-water avoidance-we observed significant muscle hyperalgesia. Finally, using the elevated plus maze to assess for anxiety level, we observed a significantly higher anxiety level in sound stress-exposed rats. Thus, unpredictable sound stress produces a condition in the rat with several features-delayed onset visceral and temporomandibular hyperalgesia and increased anxiety, as well as cutaneous and muscle hyperalgesia-commonly found in patients with fibromyalgia syndrome. PERSPECTIVE: A stress model-unpredictable sound-in the rat exhibits several features (cutaneous, musculoskeletal, and visceral hyperalgesia, as well as anxiety) that are found in patients with fibromyalgia syndrome. Thus, this model may be used to test hypotheses about the underlying mechanisms and response to therapy in patients with fibromyalgia.

Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis.

5-bromo-2-deoxyuridine (BrdU) is often used in studies of adult neurogenesis and olfactory learning, but it can also have toxic effects on highly proliferative tissue. We found that pairing Kool-Aid flavors with acute systemic injections of BrdU induced strong conditioned flavor aversions. Intermittent injections during Kool-Aid-glucose conditioning interfered with learning of a conditioned flavor-nutrient preference. Acute injection of BrdU also elevated plasma corticosterone levels and induced c-Fos in the visceral neuraxis. Thus, acute or intermittent systemic injections of BrdU (50-200 mg/kg) have aversive effects that may interfere with learning.

Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat.

We previously reported that 17ß-estradiol (E2) is pronociceptive in a visceral pain model in the rat. Subcutaneously (s.c.) administered E2 reversed the decrease in the colorectal distention (CRD)-evoked visceromotor response produced by ovariectomy (OVx) and CRD-induced nociceptive responses were greater in proestrous rats compared with met/diestrous rats. The site of action, the type of estrogen receptors activated, and the possible intracellular signaling pathway involved are yet to be established. In the present study, intrathecal (i.t.) E2 administered to OVx rats mimicked the effects of s.c. E2, suggesting that spinal estrogen receptors are involved. This is further supported by the observations that the anti-estrogen ICI 182,780 injected i.t. in intact female rats significantly decreased the visceromotor response to CRD, the response of colonic afferents was not affected by OVx, and colonic afferents did not label for estrogen receptor α (ERα). The ERα selective agonist, 4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol (PPT; s.c. or i.t.) facilitated the visceromotor response similar to E2, suggesting ERα activation is involved in mediating the pronociceptive effect of E2. PPT (s.c. or i.t.) increased the response of spinal dorsal horn neurons to CRD, indicating a spinal site of action. In addition, s.c. E2 or PPT increased CRD-induced spinal extracellular signal-regulated kinase (ERK) phosphorylation that was not observed in OVx rats and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor blocked facilitation of the visceromotor response by PPT. Taken together, the present study demonstrates that spinal ERα mediates the pronociceptive effect of E2 on visceral signal processing through activation of the MAPK pathway.

The melanocortin system is involved in regulating autonomic nerve activity through central pituitary adenylate cyclase-activating polypeptide.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptidergic neurotransmitter that is highly expressed in the nervous system. We have previously reported that a central injection of PACAP leads to changes in the autonomic nervous system tones including sympathetic excitation and parasympathetic inhibition. An anatomical study revealed that melanocortin and PACAP are colocalized in some hypothalamic nuclei. Here, we investigated the possible role of the melanocortin system in autonomic control by PACAP using SHU9119, an antagonist of the melanocortin receptors (MC3-R/MC4-R). Pretreatment with SHU-9119 did not affect the activating neural responses of adrenal, renal, and lumbar sympathetic nerves following a PACAP injection However, SHU9119 significantly eliminated the suppressing effect of a PACAP injection on gastric vagal nerve activity and excitation effects on liver and brown adipose tissue sympathetic nerve activities. These results suggest that the brain melanocortin system might play a key role in the control of thermogenic sympathetic outflows and digestive parasympathetic outflow by PACAP, but this system does not participate in the central effects of PACAP on cardiovascular function and neural activities of renal, adrenal, and lumbar sympathetic nerves.

Extrasegmental analgesia of heterotopic electroacupuncture stimulation on visceral pain rats.

Acupuncture has been applied in the clinic to treat visceral pain for a long time. However, the underlying mechanism still remains unknown. In the present study, extrasegmental analgesia of electroacupuncture (EA) at orofacial acupoints on visceral pain rats was investigated. The results revealed that nociceptive EA stimulation applied at heterotopic acupoints or nonacupoints to activate A(δ) and/or C fibers induced c-fos expression in the paratrigeminal nucleus (PTN) and significantly inhibited acetic acid-induced abdominal contractions and c-fos expression in the nucleus of the solitary tract (NTS). However, non-nociceptive EA or non-EA stimulation applied at heterotopic acupoints was totally ineffective. After infraorbital nerves transaction or pretreated by capsaicin, the EA analgesia was dramatically inhibited. Snake venom pretreatment had no influence on this analgesia. Consequently, heterotopic EA stimulation trigger the pain-inhibiting effect of diffuse noxious inhibitory controls (DNIC), in which PTN-NTS secondary neural pathway may be involved and small-diameter (A(δ) and/or C) fibers are crucial.

Sex steroids localized to the amygdala increase pain responses to visceral stimulation in rats.

UNLABELLED: Females are disproportionately affected by irritable bowel syndrome (IBS) with menstrual cycle-dependent fluctuations in abdominal pain suggesting a role for ovarian hormones. IBS patients also exhibit greater activation of brain areas involved in pain affect such as the amygdala, yet the role of supraspinal processes in the effects of ovarian hormones on visceral pain is largely unexplored. The goal of the current study was to determine whether sex steroids act at the level of the amygdala to alter colonic pain sensitivity. Ovariectomized rats received implants on the amygdala of progesterone, estradiol, progesterone combined with estradiol, or cholesterol as a control to examine the involvement of the amygdala in ovarian hormone-mediated changes in visceral sensitivity. Visceral sensitivity was quantified as the number of abdominal contractions, a visceromotor response (VMR), in response to graded pressures of colorectal distension (CRD). Somatic sensitivity was also assessed by measuring the mechanical force required to elicit hindpaw withdrawal. Elevated levels of progesterone and/or estradiol on the amygdala heightened the responsiveness to CRD; in contrast, neither estradiol nor progesterone altered somatic sensation. Furthermore, administration of progesterone or estradiol to areas adjacent to the amygdala did not affect visceral sensitivity. Future studies will address the specific steroid receptors mediating the effects of progesterone and estradiol. PERSPECTIVE: To our knowledge, this study represents the first description of a specific brain site mediating the effects of ovarian steroids on visceral sensitivity. These data also suggest that an amygdala-dependent mechanism may be responsible, at least in part, for the exacerbation of visceral symptomatology in females.

Recombinant human erythropoietin counteracts cisplatin-induced visceral hyperalgesia.

OBJECTIVE: Cisplatin exerts its cytotoxic effect through distinct DNA lesions, leading to peripheral neuropathy. The risk of sensory neuropathy is a common problem during cancer treatment with cisplatin, leading to somatic hyperalgesia. Yet, data focussing on cisplatin-induced impairment of the autonomic nervous system are limited. The present study was aimed to investigate the effect of recombinant human erythropoietin (rhEPO) on cisplatin-induced visceral hyperalgesia. METHODS: C57BL/6 mice were treated either with cisplatin (2 mg/kg, once per week) or with cisplatin (2 mg/kg, once per week) plus rhEPO (40 microg/kg, 3 times per week) for 8 weeks. Controls were treated with saline. To quantify the visceromotor response (VMR) at week 9, standardized electrodes were implanted into the external oblique musculature for electromyographic recordings. After that, animals were decapitated and dorsal root ganglia (DRG) was removed for transmission electron microscopy studies. RESULTS: Cisplatin-treated mice showed a significant increase of VMR compared to the controls [(7080 +/- 969) vs (2864 +/- 279); P< 0.001], while rhEPO dramatically counteracted this effect [(2962 +/- 336) vs (7080 +/- 969); P< 0.001)]. Transmission electron microscopy revealed cisplatin-induced structural lesions of nuclear membrane in DRG cells, which could be ameliorated by rhEPO. CONCLUSION: Erythropoietin can significantly ameliorate the cisplatin-induced visceral hyperplasia and DRG nuclear membrane structure damage in mice, indicating a neuroprotective role of erythropoietin.

Effect of pre-electroacupuncture on p38 and c-Fos expression in the spinal dorsal horn of rats suffering from visceral pain.

BACKGROUND: Acupuncture is an effective way to relieve pain, but the mechanism by which electroacupuncture (EA) decreases the visceral pain state still remains unclear. This study aimed to evaluate the effects of pre-electroacupuncture on pain behaviors, p38 phosphorylation, and c-Fos protein and mRNA expression in both the colonic wall and spinal dorsal horn of rats suffering from visceral pain. This study also investigated the probable signaling regulatory mechanism of the analgesic effect induced by electroacupuncture. METHODS: All rats were randomized into the control (Con) group, the Con + EA group, the visceral pain (VP) group, and VP + EA group (n = 8 for all groups). The visceral pain model was established using 40 microl of 5% formalin solution injected into the colon of rats. EA was applied to the bilateral Jiaji acupoints for 20 minutes before application of visceral pain. Parameters for EA were set at a continuous wave (20 Hz) and intensity where the rats shook their whiskers but did not scrabble (< or = 1 mA). The visceral pain score was recorded and the expressions of p38 and c-Fos protein were detected using Western blotting. Real-time quantitative PCR was also used to determine the expression of c-Fos mRNA. RESULTS: Rats in the VP group immediately presented with obvious visceral pain behaviors after being injected with formalin. p38 activity and c-Fos protein and mRNA expression in both the colonic wall and spinal dorsal horn were higher in the VP group than in the Con group (P < 0.05). By contrast, visceral pain behaviors were delayed in rats from the VP + EA group. p38 activity and c-Fos protein and mRNA expression were lower in the VP + EA group than that in the VP group (P < 0.01). CONCLUSIONS: Pre-electroacupuncture of the Jiaji acupoint has prophylactic analgesic effects on rats suffering from visceral pain. The p38 signal transduction pathway may be partly involved in the regulatory mechanism of this analgesic effect.

c-Fos induction by a 14 T magnetic field in visceral and vestibular relays of the female rat brainstem is modulated by estradiol.

There is increasing evidence that high magnetic fields interact with the vestibular system of humans and rodents. In rats, exposure to high magnetic fields of 7 T or above induces locomotor circling and leads to a conditioned taste aversion if paired with a novel taste. Sex differences in the behavioral responses to magnetic field exposure have been found, such that female rats show more locomotor circling and enhanced conditioned taste aversion compared to male rats. To determine if estrogen modulates the neural response to high magnetic fields, c-Fos expression after 14 T magnetic field exposure was compared in ovariectomized rats and ovariectomized rats with estradiol replacement. Compared to sham exposure, magnetic field exposure induced significantly more c-Fos positive cells in the nucleus of the solitary tract and the parabrachial, medial vestibular, prepositus, and supragenualis nuclei. Furthermore, there was a significant asymmetry in c-Fos induction between sides of the brainstem in several regions. In ovariectomized rats, there was more c-Fos expressed in the right side compared to left side in the locus coeruleus and parabrachial, superior vestibular, and supragenualis nuclei; less expression in the right compared to left side of the medial vestibular; and no asymmetry in the prepositus nucleus and the nucleus of the solitary tract. Chronic estradiol treatment modulated the neural response in some regions: less c-Fos was induced in the superior vestibular nucleus and locus coeruleus after estradiol replacement; estradiol treatment eliminated the asymmetry of c-Fos expression in the locus coeruleus and supragenualis nucleus, created an asymmetry in the prepositus nucleus and reversed the asymmetry in the parabrachial nucleus. These results suggest that ovarian steroids may mediate sex differences in the behavioral responses to magnetic field exposure at the level of visceral and vestibular nuclei of the brainstem.

Pharmacological approach to chronic visceral pain. Focus on oxycodone controlled release: an open multicentric study.

BACKGROUND AND OBJECTIVES: Visceral pain is a significant issue for patients, and the importance of treating pain is underestimated. New opioid formulations, the primary treatment option for moderate-to-severe pain, have been shown to be effective, but no studies have been conducted to address the efficacy of these agents for visceral pain. This study was conducted to determine the incidence of visceral pain in patients with uncontrolled moderate-to-severe pain, and to evaluate the efficacy of controlled-release (CR) oxycodone in this context. MATERIALS AND METHODS: s: In this multicenter, prospective, observational study, 967 of 980 evaluated patients were included, 350 (36.2%) of whom presented mainly visceral pain. In most cases (57.0%), patients had experienced pain for < or = 3 months, and the majority (94.9%) were cancer patients. Pain was uncontrolled in 340 (97.1%) patients, and was rated as severe in >2/3 of patients (mean numerical rating scale (NRS) value 7.04 +/- 1.68). Patients with uncontrolled pain were given oxycodone CR; all completed the 15-day study and no patient was switched to an alternative opioid. RESULTS: Oxycodone CR was associated with significant reductions in mean NRS value at day 3, 7 and 15 (final mean NRS 2.37 +/- 1.59) and the proportion of patients experiencing severe pain had decreased by the end of the study to 1.5%. The SF-12 questionnaire showed significant improvements in quality of life in all domains, and oxycodone CR was well tolerated. CONCLUSIONS: Oxycodone CR appears to be a very well tolerated and effective treatment for patients with visceral pain.

Vas deferens--a model used to establish sympathetic cotransmission.

The vas deferens has been used as a model for many diverse studies of different aspects of autonomic neurotransmission since its introduction including, in particular, sympathetic cotransmission involving release of ATP and neuropeptide Y together with noradrenaline and prejunctional and postjunctional neuromodulation. It has also been used to study sympathetic reinnervation following vasectomy and castration, as well as the deleterious effects of diabetes, hypertension and chronic alcohol.