Femando Cervero, Department ot Physiology University ot Alcala Madrid Spam

Visceral pain is the most common form of pain produced by disease and one of the most frequent reasons for patients to seek medical attention Yet, much of what we know about the basic mechanisms of pain derives from expenmental studies of somatic nociception However the more we know about the mechanisms of somatic and visceral sensation the more we realise that these two processes, while having many common features, also have important differences

The five main characteristics ot visceral pain are that visceral pain i) is not evoked from all viscera, 11) is not linked to visceral injury, 111) is referred to other locations iv) is diffuse and poorly localised and v) is accompanied by motor and autonomic reflexes Properties i and 11 are due to the functional attributes of the peripheral receptors that innervate different visceral organs and to the fact that many viscera are innervated by receptors whose activation does not evoke conscious Properties 111 iv and v relate to the central organisation of visceral nociceptive mechanisms, particularly to the lack of a separate visceral sensory pathway and to the low proportion of visceral afferent fibres compared to those of somatic origin

Nociceptive afferent discharges in visceral afterents evoke profound central changes Prolonged noxious stimulation ot the viscera evokes increases in the excitability ot viscerosomatic neurones in the spinal cord Such changes are very selective and highly organised as they occur only on those viscerosomatic cells that are dnven by the conditioning visceral stimulus

In somatic nociceptive systems a common correlate ot the enhanced excitability is the frequency dependant increase in neuronal excitability known as "wind up" The phenomenon of wind up is generally regarded as a display of central sensitisation However, visceral nociceptive neurones, which are quite capable of showing increased excitability on prolonged noxious stimulation, do not "wind up" as somatic neurones do thus demonstrating once again the differences between somatic and visceral nociceptive systems and casting some doubts on the role of wind up as a generator of central sensitisation and hyperalgesia

The increases in excitability of spinal cord nociceptive neurones induced by repetitive noxious stimulation may be due to the properties of the neuronal network activated by the stimuli, to the release of certain transmitters or to both Excitability increases could be mediated by positive feed-back loops between spinal and supraspmal structures These loops are particularly prominent on visceral nociceptive neurones and could be responsible for the enhanced motor and autonomic reflexes that frequently accompany visceral pain states

Substance P has long been thought to be involved with nociceptive processing, since it is expressed in small diameter primary afferents, most of which are connected to peripheral nociceptors. However, the published data on the effects of NK1 receptor antagonists in Phase 3 pain in animal models is somewhat contradictory. The recent development of mutant mice strains with dismptions of the gene coding for the NK1 receptor has provided an alternative method to investigate the role of substance P and NK1 receptors in pain. The data from experiments using receptor antagonists and from experiments in mutant mice suggest that the role of substance P and the NK1 receptor is particularly important in persistent visceral pain, especially that with a neurogenic component.

VISCERAL PAIN: EXPERIMENTAL AND CLINICAL ASPECTS

Mana Adele Giamberardino, Pathophysiology of Pain Laboratory, Department of Medicine and Science of Aging ; "G. D' Annunzio" University of Chieti, Italy.

Visceral pain is a prominent symptom in the clinical setting and one of the main reasons for patients' seeking medical care. Not only does it derive from painful diseases of single internal organs but it is often the result of concurrent algogenic conditions of more than one visceral district at a time, giving rise to complex and intricate clinical pictures.

The presentation will focus on clinical and experimental aspects of visceral pain deriving from phenomena of viscero-visceral hyperalgesia, i.e., phenomena of symptom enhancement between different visceral districts which share in part their sensory innervation, e.g., gallbladder and heart (T5), urinary tract and female reproductive organs (T10-L1).

Patients affected with ischemic heart disease tend to manifest more numerous angina attacks if they also have gallbladder calculosis compared to cardiac patients with a normal gallbladder. Similarly, fertile women with urinary stones experience a higher number of colics if they also have dysmenorrhea compared to non-dysmenorrheic women with calculosis of the same characteristics (with preferential presentation of the colics at the time of the pelvic congestion : ovulation, menstruation). In addition, dysmenorrheic women present a much higher degree of referred muscle hyperalgesia at lumbar level (area of referred pain from the upper urinary tract) than non-dysmenorrheic women even for comparable number of urinary colics experienced.

This enhancement of symptoms (pain and hyperalgesia) between visceral organs with partially overlapping sensory innervation still lacks a definite explanation. It is possible that central mechanisms (sensitization of viscero-visceral convergent neurons) play a major role in this phenomenon. However, investigation of any pathophysiological hypothesis needs availability of an animal model which closely reproduces the clinical condition. We will describe one such model, set up by combining two already existing models of visceral pathology in female rats : a model of artificial uereteric calculosis and one of experimental endometriosis (endometriosis is a frequent cause of secondary dysmenorrhea in women). Animals with the two conditions -versus animals with calculosis and sham endometriosis - display an increased number and duration of typical ureteral crises (indicative of urinary pain), as well as appearance of behavioral indicators of perceived pain from the pelvic area. They also show a much higher degree of referred lumbar muscle hypersensitivity. This appears to be the experimental counterpart of the clinical condition described in dysmenorrheic women with urinary calculosis. This model of viscero-visceral hyperalgesia can thus be usefully employed to investigate the pathophysiological bases of the phenomenon and to test appropriate kind and timing of treatments.

VISCERAL PAIN - NEW TREATMENT OPTIONS ?

Andrew S.C. Rice, Senior Lecturer in Pain Research, Imperial College School of Medicine, London, UK.

This lecture will focus on the therapeutic developments which might arise from the identification of the neurotrophin Nerve Growth Factor (NGF) as a key molecule in visceral inflammatory hyperalgesia 1. The putative role of endocannabinoids in modulating the effects of NGF will also be explored 1. This will be exemplified by reference to a model of cystitis 2 : Following bladder inflammation with turpentine a viscero-visceral hyper-reflexia develops 2, which is accompanied by increased spinal expression of the protein product of the early-immediate gene c.fos 3 and a referred hyperalgesia 4. Electrophysiological evidence of sensitisation of both primary afferent and dorsal hom neurones has also been described in this model, including recruitment of "silent" nociceptors (seel).

A number of lines of evidence point to the crucial role of NGF in visceral hyperalgesia : NGF and its mRNA are expressed in inflamed bladder tissue taken both from experimental animals 5 and patients 6. Primary afferent neurones innervating the bladder express the high affinity receptor for NGF (trkA) 7. Electrophysiological experiments demonstrate that administration of exogenous NGF directly sensitises visceral primary afferent nociceptors 8. Furthermore, intravesical administration of NGF evokes a hyper-reflexia and referred hyperalgesia identical to that seen after turpentine administration 4, 9 and provokes expression of Fos in spinal cord (seel). Finally, sequestration ofNGF attenuates the hyper-reflexia and referred hyperalgesia observed following inflammation the urinary bladder 4, 9.

The effects of NGF are thought to be predominantly mediated via trkA high affinity receptors expressed by primary afferent neurones 7. In dorsal root ganglion cells, the concentration of various neuropeptides is increased by NGF 10, which also regulates the sensitivity of nociceptors to bradykinin and vanilloids (see 1). Mast cells, which are present in inflamed bladder, appear to play an important role in amplifying the concentration of NGF and other pro-hyperalgesic mediators available for interaction with sensory neurones (see 1).

Both CB 1 and CB2 cannabinoid receptors play a role in down regulation the effects of NGF in visceral hyperalgesia : The gene encoding the neuronal CB 1 receptor has been identified in NGF-dependent primary afferent neurones 11 and endocannabinoids suppress expression of trkA 12. Furthermore, both CB2 and trkA receptors are co-expressed on mast cells 13 and the endocannabinoid palmitoylethanolamide prevents mast cell degranulation 14.

Cannabinoids reduce the hyper-reflexia associated with visceral inflammation 15. Data will be presented which demonstrate that cannabinoids also attenuate the referred hyperalgesia and Fos expression associated with cystitis. In addition, evidence which demonstrates that cannabinoids directly reduce the NGF component of visceral hyperalgesia will be discussed.

Identification of NGF as a key molecule in visceral hyperalgesia and exploitation of the role of endocannabinoids in attenuating the effects of NGF may allow the development of cannabinoid-based analgesics for use in visceral pain.

Supported by : the Medical Research Council, The Royal College of Anaesthetists, the Association of Anaesthetists and the Novartis Institute for Medical Science.

References

(1)Rice ASC. Local neuro-immune interactions in visceral hyperalgesia : bradykinin, neurotrophins and cannabinoids. In : Bountra C, Schmidt W, Munglani R, eds. Pain : Current understanding, emerging therapies and novel approaches to drug discovery. New York : Marcel Dekker, 2000.

(2) McMahon SB, Abel C. A model for the study of visceral pain states : chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals. Pain 1987 ; 28 : 109-127.

(3) Birder LA, de Groat WC. Increased c-fos expression in spinal neurones after irritation of the lower urinary tract in the rat. J Neuroscience 1992 ; 12 : 4878-4883.

(4) Jaggar SI, Scott HCF, Rice ASC. Inflammation of the rat urinary bladder is associated with a referred thermal hyperalgesia which is Nerve Growth Factor dependant. Br J Anaesth 1999 ; 83 : 442-448.

(5) Oddiah D, Anand P, McMahon SB, Rattray M. Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder. Neuroreport 1998 ;9: 1455-1488.

(6) Lowe EM, Majithia AA, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osbome JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. British Journal of Urology 1997 : 79 : 572-577.

(7) McMahon SB, Armanini MP, Ling LH, Phillips HS. Expression and coexpression of trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets. Neuron 1994 : 12 : 1161-1171.

(8) Dmitrieva N, McMahon SB. Sensitisation of visceral afferents by nerve growth factor in the adult rat. Pain 1996 ; 66 : 87-97.

(9) Dmitrieva N, Shelton D, Rice ASC, McMahon SB. The role of nerve growth factor in a model of visceral inflammation. Neuroscience 1997 ; 78 : 449-459.

(10) Donnerer J, Schuligoi R, Stein C. Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue : evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 1992 : 49 : 693-698.

(11) Friedel RH, Schnurch H, Stubbusch J, Barde Y. Identification of genes differentially expressed by nerve growth factor and neurotrophin-3 dependent sensory neurons. Proc Nati Acad Sci U S A 1997 ; 94 : 12670-12675.

(12) Meick D, De Petrocellis L, Orlando P, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 2000 ; 141 : 118-126.

(13) Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Nati Acad Sci LJ S A 1995 : 92 : 3376-3380.

(14)Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-Hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-regulating mast cell activation. Eur J Pharmacol 1996 : 300 : 227-236.

(15) Jaggar SI, Hasnie FS, Sellaturay S, Rice ASC. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide investigated in models of visceral and somatic inflammatory pain. Pain 1998 ; 76 : 189-199.

THE MANAGEMENT OF CHRONIC REFRACTORY ANGINA: A CARDIOLOGIST'S PERSPECTIVE

Michael R Chester, David D Trenbath, Austin A Leach. National Refractory Angina Centre - Liverpool.

Chronic refractory angina is one of the most rapidly growing clinical problems in cardiology. The diagnosis is based upon the presence of angina "thought" to be caused by myocardial ischaemic despite optimal medical therapy and when revascularisation is not feasible.

The conventional diseased centred model of treatment is (by definition) inadequate and must give way to a more appropriate treatment model. One of the major challenges is to persuade cardiologists and cardiac surgeons of the need to abandon their tried and tested ischaemia centred model of treatment. In the first of two presentations we will provide an insight into the development of the anti-ischaemia model and how it leaves deep scars on the patient and carers suffering with chronic refractory angina. In the second section we will concentrate on the development and impact of the multidisciplinary patient centred model of treatment.

For detailed information on all aspects of chronic refractory angina see website www. angina, org

RECTAL SENSITIVITY ASSESSED BY A REFLEXOLOGIC TECHNIQUE IN HUMANS: FURTHER EVIDENCE FOR TWO TYPES OF MECHANORECEPTORS.

D. Bouhassira. J.M.Sabate, D. Le Bars, B. Coffin, R. Jian. INSERM U-161 and INSERM U-290, Paris, France.

Aim of investigation : We previously showed that slow ramp rectal distensions induce graded inhibitions of the somatic nociceptive RIII reflex recorded from the lower limb, which correlated with both distension volume and visceral sensation. In contrast, rapid phasic rectal distensions induced facilitatory or biphasic effects (i.e., facilitations followed by inhibitions) depending on the level of distension. The aim of the present study was to examine the role of mucosal and serosal rectal mechanoreceptors in these viscerosomatic interactions.

Methods : Following approval by a local Ethics Committee, we analyzed, in 6 healthy volunteers, the effects of both types of rectal distensions on the RIII reflex, after topical application of lidocaine or placebo administered in a double-blind and crossover fashion.

Results : Inhibitions of the RIII reflex induced by both slow ramp and rapid distensions were strongly reduced after administration of lidocaine, but not after placebo. In contrast, facilitations of the RIII reflex observed during the initial phase of rapid distensions, were not modified after lidocaine or placebo applications.

Conclusions : These results suggest that inhibitions, but not facilitations, of the nociceptive RIII reflex triggered by rectal distensions, depend preferentially on the activation of superficial mucosal receptors. This reflexologic technique might thus represent an interesting tool for studying the role of the different rectal mechanoreceptors involved in visceral sensations.

NEURAL CORRELATES OF RECTAL PAIN IN IBS PATIENTS: AN fMRI STUDY

B Bonaz. M Baciu , E Papillon, C Segebarth, R Bost, JP Le Bas, J Foumet. Dept of GastroenterologyJNSERM U 438, CHU, 38043 Grenoble Cedex 09, France.

Numerous arguments favour a role of the central nervous system in the chronic visceral hyperalgesia observed in patients with irritable bowel syndrome (IBS) (1). We recently characterized, in healthy volunteers, cerebral loci activated by a rectal distension (insula, anterior cmgulate and dorso-lateral prefrontal cortices) (2).

Aim: to characterize, using fMRI, cerebral loci activated by a rectal distension in IBS patients.

Methods: 12 right-handed patients were consecutively recmited The paradigm alternated three times a control period, where a rectal balloon was completely deflated (1 min), and a stimulus period (1 min) where the balloon was inflated. fMRI was performed at 1.5T (Philips all body, equipped with echoplanar imaging). Twenty five adjacent axial sections, centred and parrallel to the bicommissural plane were measured 14 times dunng each period. An anatomic scan was performed at the end to identify cerebral regions. Data were analyzed by statistical parametric mapping software.

Results: the group analysis showed a) no significant cerebral activation, b) significant desactivations (P<0,01) in the right insula, right amygdala, and right striatum.

Conclusions: in IBS patients, cerebral desactivations are observed in loci involved in the modulation of visceral pain (insular cortex) and emotional life (amygdala) (1) Gastroenterology 107: 271-293, 1994. (2) Am J Neuroradiol, 20 :1920-1924, 1999.

Acknowledgments: supported by Joseph Fourier University

ACUTE PANCREATITIS IN BULGARIAN POPULATION - GENETIC PREDISPOSITION, PAIN SYNDROME AND TREATMENT.

Petar Petrov. I. Zanzov, T. Stoev, E. Zanzov, G. Stankova, P. Boyadjieva. Dept. of general surgery, Dept. of biochemistry: Higher Medical Institute, Plovdiv, 4000, V.Aprilov str. 15-, BULGARIA

Aim of investigation: To investigate the mutations with alpha 1-AT gene in patients with acute pancreatitis and the relationships between pain and treatment.

Methods: Immunoenzyme method to determine alpha 1-AT ; phenotypmg, conservative, intraarterial and surgical therapy.

Results: Geneticaly determined deficiency of alpha 1-AT was observed in 12 patients of the 70 under study. This deficiency is higher (14,28 %) than the bulgarian standard (4,95 %). Phenotyping of the same group shows the next genetic combinations with alpha 1-AT: MM-47, MS-4, MZ-2.SS-7.ZZ-10.

Conclusions: The frequency of the alpha 1-AT variants is significantly higher in patients with recurrent acute pancreatitis. Alcoholism, diet, holelithiasis cause autodigestion of the gland and pain. Treatment with protease inhibitors is needed to reestablish the normal balance.

EFFECT OF TRIMEBUTINE ON THE VISCERAL SENSITIVITY IN PATIENTS WITH IRRITABLE BOWEL SYNDROME (IBS)

M. Boivin. B. Scherrer, J. Spenard. 'Hopital Saint-Luc, Universite de Montreal, Parke-Davis, Paris, Axcan Pharma, Montreal

Recent animal studies have shown that trimebutine (TMB), a peripheral receptor agonist, has an analgesic effect on visceral nociception in addition to motility regulation.

The aim of our study was to determine the effect of TMB on visceral sensitivity in IBS patients with a predominance of constipation.

Method: 20 IBS patients who fulfilled the Rome I criteria (13 women and 7 men; mean age: 40) participated in the double-blind, randomized, cross-over, placebo controlled study. Two experiments were done 7 days apart where a balloon was inserted in the rectum. After baseline was measured, rectal balloon was then progressively inflated (4mmHg increment) until the patient perceived a pain of grade 3 (sustained moderate pain) or until the maximal pressure of 48mmHg was achieved. For each experiment, patients randomly received either an i.v. bolus of lOOmg TMB or placebo, followed by an infusion of 3.33mg/min of TMB or placebo during the inflation of the balloon. The endpoint was the pressure at which the grade 3 pain was reached. The main statistical analysis was performed on the ITT population and consists of a mixed model analysis of variance for coping with missing values.

Results: Patients received a mean dose of 169mg when on TMB. The difference between the first fell grade 3 pain and the baseline was statistically significant for the ITT analysis (TMB: 30.7±2.1mmHg; placebo: 26.6±2.1mmHg; p=0.0492) and for the set of 11 patients who reached grade III at each period (TMB: 29.5±2.8mmHg; placebo: 25.1 ± 3.3mmHg; p=0.0469).

Conclusion: This study shows that perfusion of TMB has an effect on the viscero-sensitivity in IBS patients as assessed by rectal distension method.

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 98, 99, 124, 165, 220, 221, 245, 255.