2010 Visceral Referred Pain

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OTHER SOFT TISSUE DISORDERS

Visceral Referred Pain

Maria Adele Giamberardino

Giannapia Affaitati

Raffaele Costantini

ABSTRACT. Objectives: The perception of pain in regions other than the affected organ is therule in visceral nociception. This paper reviews the current knowledge about modalities of clinicalpresentation and pathophysiological mechanisms of visceral referred pain, based on the results of clinical and experimental studies.

Findings: Visceral referred pain occurs in somatic areas neuromerically connected with theaffected organs where secondary hyperalgesia takes place mostly in deep body wall tissues,extending to superficial layers in repetead/prolonged visceral processes. When two internal organssharing part of their central sensory projection are affected, visceral pain and referred hyperalgesiafromeach organ are significantly enhanced [“viscero-visceral hyperalgesia”]. In this case, treatmentof one visceral condition significantly improves symptoms from the other. Referred phenomenaare mainly sustained by central sensitization processes, involving viscero-somatic or viscero-visceral-somatic convergent neurons, as shown by electrophysiological studies in animal models.A contribution by viscero-somatic reflexes is also present, which would account for the trophic

changes of deep body wall tissues that often accompany the hyperalgesia.The expression of visceral referred pain is reduced with the aging process, which renders

diagnosis more difficult in the elderly, increasing the risks in life-threatening conditions. Someof the contributing mechanisms may include age-related impaired A-Delta fiber function and areduction in the content and turnover of neurotransmitter systems involved in nociception.

Conclusions: Visceral referred pain and accompanying phenomena are being increasinglyunderstood as regards their pathophysiology. This opens new avenues for treatment strategies thatare more mechanism-based and not purely symptomatic.

KEYWORDS. Visceral referred pain, hyperalgesia, central sensitization, viscero-visceral hy-peralgesia

Maria Adele Giamberardino and Giannapia Affaitati, Ce.S.I, “G. D’Annunzio” Foundation, Department of Medicine and Science of Aging, “G. D’Annunzio” University of Chieti, Chieti, Italy.

Raffaele Costantini, Institute of Surgical Pathology, “G. D’Annunzio” University of Chieti, Chieti, Italy.Address correspondence to: Maria Adele Giamberardino, MD, Pathophysiology of Pain Laboratory, via Carlo

de Tocco n. 3, 66100 Chieti, Italy, Phone: +39-0871-358070, Fax: +39-0871-541207. E-mail: [email protected]

Journal of Musculoskeletal Pain, Vol. 18(4), 2010Available online at www.informaworld.com/MUP

© 2010 Informa Healthcare USA, Inc. All rights reserved.doi: 10.3109/10582452.2010.502624 403



404 JOURNAL OF MUSCULOSKELETAL PAIN

INTRODUCTION

Pain originating in internal organs is amongstthe most frequent forms of pain experienced byindividuals in the course of life. Cardiac pain

from coronary heart disease, urinary and bil-iary colics from calculosis, abdominal pain fromirritable bowel syndrome [IBS], or pelvic painfrom the reproductive area, especially in women,are only a few examples of this variegated re-ality (1). Visceral pain has the distinctive fea-ture of being perceived in areas of the body lo-cated at a distance from the diseased organs.Henry Head [1893] labelled this phenomenon“referred pain,” a painful sensation reported ina region other than that in which the noxiousstimulation takes place. While the patterns of re-ferral vary from organ to organ, the mechanisms

behind visceral referred pain are fundamentallythe same whatever the viscus in question, asare the rules to be applied when interpretingthe various modalities of its clinical presenta-tion (2, 3). This paper is intended to highlightthe clinical profile of referred pain from visceraand its current interpretation, based on the find-ings of clinical and experimental studies in thefield.

Clinical Presentation of Visceral Referred Pain

The very first phase of painful episodes frominternal organs is similar in any visceral paincondition: a vague and poorly defined sensationfelt at the midline, accompanied by markedneurovegetative reactions and emotional signs[true visceral pain] (4). True visceral pain isalways transitory, lasting from minutes to hours,after which the phase of referral occurs, whichvaries and is organ-specific. Visceral referredpain is, in fact, perceived in somatic areas of the body wall located in the same neuromericfield as the organ in question, for example, leftchest area/arm/forearm for the heart, lumbarregion/flank for the urinary tract, upper rightabdominal quadrant for the biliary tract, lowestabdominal quadrants for the reproductiveorgans. Secondary hyperalgesia [increasedsensitivity to painful stimuli/decreased painthreshold] most often takes place in the referredareas, starting in the skeletal muscle layer, andextending upward to the overlying subcutis

and skin especially in the case of recurrentand/or prolonged visceral stimuli [referred painwithout and with hyperalgesia] (5).

The hyperalgesia can be detected by clinicalmeans and precisely quantified instrumentally.

Clinical manoeuvres reveal the hypersensitivityin an “on-off” manner, i.e., vigorous pain re-action by the subject upon firm manual com-pression of the muscle tissue, pinch palpationof the subcutis, scratching of a needle pointover an area of altered dermographic reactiv-ity of the skin. Instrumental procedures involvepain threshold measurement to different stim-uli, with a threshold decrease indicating hyper-algesia. For muscle and subcutis, mechanical[pressure and pinch algometer], electrical [im-pulses delivered through needle electrodes], andchemical [injections of algogenic substances of

progressively increasing concentrations] stimuliare usually employed. For skin, thermal stimu-lation [thermal algometer] is also used in addi-tion to mechanical [von Frey hairs] and electrical[impulses delivered through surface electrodes]stimuli (1, 2, 5–7).

The profile of referred hyperalgesia has beenassessed by using these different procedures inpatients with different pathologies of internal or-gans, e.g., coronary artery disease, gallbladderdisease, IBS, urinary calculosis, dysmenorrhea,and endometriosis (5, 7–10). On the whole, theresults of these studies indicate that referred vis-

ceral hyperalgesia, mostly involving the skeletalmuscle layer, only appears in the case of painfulvisceral diseases, independently of their organicor dysfunctional nature. Hyperalgesia is alreadydetectable after a few visceral pain episodes, isaccentuated in extent by the repetition of theepisodes, and outlasts not only the spontaneouspain but often also the presence of the primarypain trigger in the internal organ. In urinary cal-culosis, for instance, lumbar muscle hyperalge-sia appears soon after the first one or two colics,increases with their repetition, is detectable be-tween the painful episodes, and in 90 percent of the cases persists for months–years after elimi-nation of the urinary stone (10).

In acute inflammatory visceral pain, the re-ferred hyperalgesia tends to also involve thesuperficial somatic tissues. Patients with acuteappendicitis show increased ratings to pinprick and thermal stimuli, together with a reduc-tion of cutaneous electrical pain thresholds andmuscle pressure pain thresholds in the referred




animal models. Human studies have been con-ducted in healthy volunteers by applying con-trolled stimuli of different nature to various in-ternal organs (6, 15–17). In these studies, thedistribution of the evoked pain was character-

ized and the phenomenon was also shown of theenlargement of the referred areas after “sensiti-zation” of the viscera due to repeated stimula-tion or experimental inflammation of the organs[“visceral hyperalgesia”]. For instance, repeatedfilling of the urinary bladder in female volun-teers progressively increased the physiologicaland perceptual responses to pain and the extentof the referred somatic areas (18), continuouselectrical stimulation of the gut provoked a pro-gressive enlargement of the referred pain areaas the duration of the stimulation was increasedfrom 30 to 120 seconds (15) and thermal, me-

chanical, and electrical stimulation of the oe-sophagus after chemical sensitization resulted ina significant increase in the referred pain areasin human volunteers, a result indicating centralsensitization phenomena (19, 20).

Various animal models have also been setup to study referred phenomena from viscera(21). The parameter monitored has mostly beenreferred deep and/or superficial hyperalgesia,assessed by recording withdrawal reactions toapplication of mechanical and thermal stimulior by measuring vocalization thresholds to dif-ferent stimuli [mechanical, electrical], since vo-calization is a highly integrated test, regardedas a reliable index of perceived pain in ani-mals (21). Some examples are here provided.Prolonged nociceptive electrical stimulation orformation of an artificial stone in one ureterin rats produces not only behavioral signs in-dicative of direct visceral pain but also referredhypersensitivity of the ipsilateral oblique mus-culature [L1], as shown by a significant re-duction of vocalization thresholds to electricalmuscle stimulation. In calculosis rats, the ex-tent of this threshold decrease is proportional to

the amount of spontaneous pain behavior andis dose-dependently reduced by treatment withmorphine, tramadol, metamizol, nonsteroidalanti-inflammatory drugs [NSAIDs], or spas-molytics (22, 23).

The combination of an artificial ureteric stonewith experimental emdometriosis in female ratsproduces particularly pronounced algogenic ef-fects. In this model, mimicking the “viscero-visceral hyperalgesia” observed in women with

urinary calculosis and endometriosis, an en-hancement is, in fact, observed not only of thespontaneous pain behavior from both the ureterand the reproductive area but also of the referredlumbar muscle hyperalgesia, with a post-stone

decrease in vocalization thresholds to electri-cal muscle stimulation significantly more pro-nounced than inratswith a stone only or ratswithsham-endometriosis plus stone. Similar to whatis observed in humans, treatment of only onecondition in this model relieves symptoms fromthe other, i.e., treatment of endometriosis beforestone formation [with NSAIDs or tramadol] pre-vents the enhancement of pain behavior fromthe ureter [“ureteral crises” and referred lumbarmuscle hyperalgesia] (24).

Experimental inflammation of the bladder inrats and mice also produces referred hyperalge-

sia to various stimuli in the tail, caudal abdomenor hindlimb (25–28).

Inflammation of the uterus in female rats elic-its not only spontaneous pain behavior but alsoreferred hyperalgesia in the ipsilateral flank mus-cles, as testified by a significant decrease in vo-calization thresholds to electrical muscle stimu-lation. In this model, mimicking women’s pelvicinflammatory pain, the areas of referred mus-cle hyperalgesia are also the site of neurogenicplasma extravasation in the skin, the first exper-imental evidence of trophic changes in sites of referred pain from viscera (29, 30). Neurogenicplasma extravasation in L5 to S2 dermatomes[primarily in L6 and S1] has also been docu-mented in male rats after experimental prostati-tis [chemical irritation of the prostate] and in ratsreceiving bladder irritation (31).

Chronic pancreatitis induced in rats by pan-creatic infusion of trinitrobenzene sulfonic acidproduces increased sensitivity to mechanicalprobing of the abdomen [referred hyperalgesia]in addition to increased sensitivity to noxiouselectrical stimulation of the pancreas (32).

In the mouse, chemical stimulation of the

colon evokes dose-dependent visceral pain be-haviors [licking of abdomen, stretching, contrac-tions of abdomen, etc.] and referred abdominalhyperalgesia, as shown by a significant increasein withdrawal responses to application of vonFrey hairs to the abdomen (33).

Electrophysiological, pharmacological, ana-tomical, immunohistochemical, and genetic in-vestigations performed on these and other ani-mal models of visceral nociception have allowed



Giamberardino et al. 407

several hypotheses on the pathophysiology of re-ferred phenomena to be tested in standardizedexperimental contexts (22, 34, 35).

Pathophysiology of Visceral Referred Pain

The referral of visceral sensations to areas of the body away from the injured organ has beeninterpreted as the consequence of convergenceof somatic and visceral afferent information ontothe same sensory neurons. The brain receives in-formation from both internal organs and somaticareas through the same sensory channel, butwould attribute the origin of the sensation to thesomatic domain because of mnemonic traces of previous experiences of somatic pain, more nu-merous in percentage than those of visceral painin the course of life [convergence-projection the-

ory]. The pattern of referral will be determinedby the pattern of viscero-somatic convergenceso that, for example, if neurons with inputs fromcardiac nociceptors have receptive fields in theleft thorax and left arm, then the pain will be feltin these regions of the body rather than in theheart. Considerable experimental evidence is insupport of this interpretation as numerous stud-ies have described viscero-somatic convergentneurons in the spinal cord and other regions of the CNS (34).

When the nociceptive input from the affectedinternal organ is particularly strong, prolonged

or repetitive, an “irritable focus,” in modernterms, a state of “central sensitization”, is sec-ondarily set off in the spinal cord. This involvesphenomena of increased spontaneous activity inviscero-somatic convergent neurons, an increasein neuronal response evoked by large- and small-caliber primary afferent fibers and enlargedreceptive field areas (36). “Central sensitization”accounts in part for the referred hyperalgesiathat so often accompanies visceral pain states.With hyperactivity and hyperexcitability of viscero-somatic convergent neurons induced bythe massive afferent visceral barrage, in fact,the central effect of even normal sensory inputscoming from the somatic area of referral wouldbe facilitated [convergence-facilitation theory](22, 34). Central sensitization has, indeed, beendocumented in electrophysiological studies inanimal models of referred muscle hyperalgesiafrom viscera, such as the model of artificialureteric calculosis, in which the rats display hy-persensitivity of the oblique musculature ipsilat-

eral to the implanted ureter (37), and N-methyl-D-aspartate receptors are assumed to play animportant role in this central process (34).

A similar mechanism has been hypothesizedfor referred hyperalgesia in the case of concur-

rent algogenic conditions from two internal or-gans sharing at least part of their central sen-sory projection [viscero-visceral hyperalgesia](1). Along with viscero-somatic convergence, infact, experimental evidence exists for viscero-visceral convergence in the CNS, e.g., betweenthe gallbladder and heart, between colon/rectum,bladder, vagina, and uterine cervix (13, 38, 39).Thus, increased excitability of viscero-visceral-somatic convergent neurons, triggered by the af-ferent barrage from one visceral organ, couldmediate the increased reactivity to impulsesfrom the second visceral organ and the somatic

area of referral (1, 2). Preliminary electrophysi-ological studies in the animal model of referredhyperalgesia from endometriosis plus ureteralcalculosis have provided evidence for a higherlevel of sensitization of sensory neurons receiv-ing input from the hyperalgesic muscle withrespect to rats with sham endometriosis plusureteral calculosis and rats with calculosis only(4). Further experiments are, however, neededto fully characterize the central components of referred phenomena in viscero-visceral hyper-algesia, as well as to investigate the possiblecontribution by other mechanisms.

Central changes after noxious visceral inputcan also induce the release of vasoactive pep-tides from fine afferents in peripheral tissuesnot affected by the original cause, via dorsalroot reflexes conducted antidromically from thespinal cord (40). The central changes producedby the visceral input could thus not only be re-sponsible per se for the secondary hyperalgesia[increased responsiveness of sensitized viscero-somatic convergent neurons to painful stimuliin the somatic area of referral], but also con-tribute to the phenomenon via dorsal root re-

flexes which are conducted centrifugally out toperipheral sensory endings, where they can re-lease neurotransmitters or alter the excitabilityof sensory terminals related to the referred area.

The mechanisms so far described seem, how-ever, not sufficient to explain in full the phe-nomena that take place in the visceral referredpain areas, especially the trophic changes whichcannot be accounted for on the basis of centralmechanisms only.




Regarding the skeletal muscle, a reflex arc ac-tivation has been postulated, involving sensoryfibers from the internal organ, as afferent branchof the reflex, and somatic efferences to the skele-tal muscle, as efferent branch of the reflex. This

hypothesis would also fit with the clinical obser-vation that the area of pain referral from viscerais often the site of sustained muscle contraction(5). The activation of somatic efferences wouldthus produce sustained contraction in the skele-tal muscle, in turn responsible for sensitizationof nociceptors locally, which could contribute tothe hyperalgesia and in the long run also to thedecreased thickness of the tissue. Experimen-tal support for this theory has been provided bystudies in the rat model of referred muscle hy-peralgesia from artificial ureteric calculosis inwhich positivity was found of a number of ul-

trastructural indices of contraction in the hyper-algesic muscle ipsilateral to the affected ureterat lumbar level but not in the contralateral, non-hyperalgesic muscle. The extent of change inthese indices was proportional to the degree of visceral pain behavior and referred hyperalgesiarecorded in the animals. In the same model, c-Fos activation was found in the spinal cord notonly in sensory neurons but also in motoneurons,significantly more on the affected side (41, 42).

Reflex arc activations have been claimedto be contributing mechanisms also to theskin/subcutis hyperalgesia. In this case, the ef-ferent branch of the reflex would be representedby sympathetic efferences toward the superficialsomatic tissues. This hypothesis, based on theclinical observation of the reduction of referredsuperficial sensory changes in patients afterblocking of the sympathetic efferences towardthe referred area, still needs to be confirmed ex-perimentally in standardized conditions (2, 43).

The exact nature of referred trophic changesin the subcutis remains to be determined, but thefact that these tend to persist almost unalteredfor a long time after cessation of the painful

episodes could indicate some structural tissuealteration which is liable to become permanentin spite of resolution of the visceral condition.Since compression on the thickened tissue doesnot leave the typical depression of edema due tointerstitial fluid accumulation [“fovea”], it hasbeen hypothesized that the thickening is due toan increase in solid tissue pressure that is exertedon the points of contact of the cells, fibers, colla-gen, and intercellular gel, this pressure being an

expression of the resistance that solid structuresof the tissue offer to atmospheric pressure. Thisaugmentation in pressure would be motivated byan increase in subcutis interstitial jaluronic acid(7). Further studies on bioptic tissue samples will

be needed to clarify this issue.

Visceral Referred Pain as a Function of Age

The aging process is associated with a lesserexpression of visceral pain in general, and acutereferred pain in particular. This phenomenonparadoxically occurs when an increase is ob-served, with advancing age, of a number of pathologic conditions that are potentially al-gogenic for viscera (44). Atherosclerosis, forexample, increases exponentially with age but is

not accompanied by a parallel increase in mani-festations of ischemic pain from internal organs:silent cardiac ischemia and painless myocardialinfarction become more frequent in older age(45). This phenomenon of silent or atypical pre-sentation of ischemic heart disease makes diag-nosis in the elderly more difficult. About 45 per-cent of older adults with appendicitis do not havereferred lowerright quadrant pain as a presentingsymptom, compared to less than five percent of younger adults (46). Also, visceral referred painassociated with various types of malignancy isreported to be much less intense in adults of ad-

vanced age than in younger adults (47). Studiesin experimental animal models also confirm areduction of visceral pain expression with theaging process, as shown by a decreased painbehavior in aged rats with artificial ureteral cal-culosis with respect to young rats [unpublishedobservation].

The pathophysiology of the decreasedexpression of referred visceral pain in olderage is being actively investigated, some of thecontributing mechanisms may include impairedA-Delta fiber function and a reduction inthe content and turnover of neurotransmittersystems known to be involved in nociception[e.g., substance P or calcitonin gene-relatedpeptide] (48). Also worth mentioning is thehigher prevalence, in the elderly, of medicalconditions, such as hypertension or diabetes,which has definitely been associated with animpaired pain perception (49). Thus, elderlypatients affected with these conditions are at ahighest risk of presenting with painless diseases



Giamberardino et al. 409

of internal organs, a circumstance that shouldalways be kept in mind clinically to avoid notonly misdiagnosis but mostly underestimationof potentially life-threatening visceral events.

CONCLUSION

Referred pain and hyperalgesia from internalorgans have been known for a long time clini-cally, but their precise assessment in patients andinvestigation of their pathophysiological mech-anisms in standardized conditions in both hu-man and animal models have been performedin relatively recent times. The controlled studiescarried out in the past few decades have now al-lowed a considerable advancement in the under-standing of these phenomena. Though a number

of questions still remain open in the field, such asthe precise identification of mechanisms beyondviscero-visceral hyperalgesia, the information sofar available represents an important basis for theinstitution of therapeutic regimens that are moremechanism-based and not merely symptomaticin patients affected with such an important andfrequent form of suffering as visceral pain.

Declaration of interest: The author reports noconflict of interest. The author alone is respon-sible for the content and writing of this paper.

REFERENCES

1. Giamberardino MA, Affaitati G, Costantini R:Referred pain from internal organs. Handbook of Clini-cal Neurology. Edited by F Cervero, TS Jensen. Elsevier,Edinburgh, 2006, pp. 343–361.

2. Giamberardino MA, Cervero F: The neural basisof referred visceral pain. Chronic Abdominal and Vis-ceral Pain: Theory and Practice. Edited by PJ Parischa,WD Willis, GF Gebhart. Informa Healthcare, NewYork,2007, pp. 177–192.

3. Sengupta JN: Visceral pain: The neurophysiolog-ical mechanism. Handb Exp Pharmacol 194: 31–74,2009.

4. Giamberardino MA, Costantini R: Visceral painphenomena in the clinical setting and their interpre-tation. Visceral Pain: Clinical, Pathophysiological andTherapeutic Aspects. Edited by MA Giamberardino.Oxford University Press, Oxford, 2009, pp. 9–20.

5. Vecchiet L, Giamberardino MA, Dragani L,Albe-Fessard D: Pain from renal/ureteral calculosis:Evaluation of sensory thresholds in the lumbar area.Pain 36: 289–295, 1989.

6. Arendt-Nielsen L: Induction and assessment of experimentalpain from human skin, muscleand viscera.Proceedings of the 8th WorldCongress on Pain, Progressin Pain Research andManagement.Edited by TS Jensen,JA Turner, Z Wiesenfeld-Hallin. IASP Press, Seattle,1997, pp. 393–425.

7. Giamberardino MA, Affaitati G, Lerza R,Lapenna D, Costantini R, Vecchiet L: Relationship be-tween pain symptoms and referred sensory and trophicchanges in patients with gallbladder pathology. Pain114: 239–249, 2005.

8. Caldarella MP, Giamberardino MA, Sacco F,Affaitati G, Milano A, Lerza R, Balatsinou C, LaterzaF, Pierdomenico SD, Cuccurullo F, Neri M: Sensitivitydisturbances in patients with irritable bowel syndromeand fibromyalgia. Am J Gastroenterol 101: 2782–2789,2006.

9. Giamberardino MA, De Laurentis S, Affaitati G,Lerza R, Lapenna D, Vecchiet L: Modulation of pain andhyperalgesia from the urinary tract by algogenic condi-

tions of the reproductive organs in women. NeurosciLett 304: 61–64, 2001.10. Vecchiet L, Giamberardino MA, de Bigontina P:

Referred pain from viscera: When the symptom persistsdespite the extinction of the visceral focus. Adv PainRes Ther 20: 101–110, 1992.

11. Stawowy M, Rossel P, Bluhme C, Funch-JensenP, Arendt-Nielsen L, Drewes AM: Somatosensorychanges in the referred pain area following acute inflam-mation of the appendix. Eur J Gastroenterol Hepatol 14:1079–1084, 2002.

12. Stawowy M, Bluhme C, Arendt-Nielsen L,Drewes AM, Funch-Jensen P: Somatosensory changesin thereferredpain area in patients with acute cholecysti-tis before and after treatment with laparoscopic or open

cholecystectomy. Scand J Gastroenterol 39: 988–993,2004.

13. Foreman RD: Neurological mechanisms of chestpain and cardiac disease. Cleve Clin J Med 74(1):S30–S33, 2007.

14. Loeser JD: Bonica’s Management of Pain. Lip-pincott, Williams & Wilkins, Philadelphia, 2001.

15. Arendt-Nielsen L, Drewes AM, Hansen JB, Tage-Jensen U: Gut pain reactions in man: An experimentalinvestigation using shortand long duration transmucosalelectrical stimulation. Pain 69: 255–262, 1997.

16. Drewes AM,Schipper KP, Dimcevski G, PetersenP, Andersen OK, Gregersen H, Arendt-Nielsen L: Mul-timodal assessment of pain in the esophagus: A newexperimental model. Am J Physiol Gastrointest LiverPhysiol 283: 95–103, 2002.

17. Drewes AM,Schipper KP, Dimcevski G, PetersenP, Gregersen H, Funch-Jensen P, Arendt-Nielsen L: Gutpain and hyperalgesia induced by capsaicin: A humanexperimental model. Pain 104: 333–341, 2003.

18. Ness TJ, Richter HE, Varner RE, Fillingim RB:A psychophysical study of discomfort produced by re-peated filling of the urinary bladder. Pain 7: 661–669,1998.




19. Olesen AE, Staahl C, Brock C, Arendt-Nielsen L,Drewes AM: Evoked human oesophageal hyperalgesia:A potential tool for analgesic evaluation? Basic ClinPharmacol Toxicol 105: 126–36, 2009.

20. Pedersen J, Reddy H, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, DrewesAM: Cold andheat pain

assessment of the human oesophagus after experimentalsensitisation with acid. Pain 110: 393–399, 2004.

21. Le Bars D,Gozariu M,Caaden SW: Animal mod-els of nociception. Pharmacol Rev 53: 597–652, 2001.

22. Cervero F, Laird JMA: Understanding the signal-ing and transmission of visceral nociceptive events. JNeurobiol 61: 45–54, 2004.

23. Giamberardino MA, Valente R, de Bigontina P,Vecchiet L: Artificial ureteral calculosis in rats: Be-havioural characterization of visceral pain episodes andtheir relationship with referred lumbar muscle hyperal-gesia. Pain 61: 459–469, 1995.

24. Giamberardino MA, Berkley KJ, Affaitati G,Lerza R, Centurione L, Lapenna D, Vecchiet L: Influ-

ence of endometriosis on pain behaviors and musclehyperalgesia induced by a ureteral calculosis in femalerats. Pain 95: 247–257, 2002.

25. Bon K, Lichtensteiger CA, Wilson SG, Mogil JS:Characterization of cyclophosphamide cystitis, a modelof visceral and referred pain, in the mouse: Species andstrain differences. J Urol 170: 1008–1012, 2003.

26. Jaggar SI,ScottHC, Rice AS:Inflammationof therat urinary bladder is associated with a referred thermalhyperalgesia which is nerve growth factor dependent.Br J Anaesth 83: 442–448, 1999.

27. McMahon SB, Abel C: A model for the study of visceral pain states: Chronic inflammation of the chronicdecerebrate rat urinary bladder by irritant chemicals.Pain 28: 109–127, 1987.

28. Olivar T, Laird JM: Cyclophosphamide cystitis inmice: Behavioural characterisation and correlation withbladder inflammation. Eur J Pain 3: 141–149, 1999.

29. Wesselmann U, Czakanski PP, Affaitati G,Giamberardino MA: Uterine inflammation as a noxiousvisceral stimulus: Behavioral characterization in the rat.Neurosci Lett 246: 73–76, 1998.

30. Wesselmann U, Lai J: Mechanisms of referredvisceral pain: Uterine inflammation in the adult virginrat results in neurogenic plasma extravasation in theskin. Pain 73: 309–317, 1997.

31. Ishigooka M, Zermann DH, Doggweiler R,Schmidt RA: Similarity of distributions of spinal c-Fosand plasma extravasation after acute chemical irritationof the bladder and the prostate. J Urol 164: 1751–1756,2000.

32. Winston JH, He ZJ, Shenoy M, Xiao SY, PasrichaPJ: Molecular and behavioral changes in nociception ina novel rat model of chronic pancreatitis for the studyof pain. Pain 117: 214–222, 2005.

33. Laird JMA, Martinez-Caro L, Garcia-Nicas E,Cervero F: A new model of visceral pain and re-ferred hyperalgesia in the mouse. Pain 92: 335–342,2001.

34. Cervero F: Mechanisms of visceral pain. An up-dated review: Refresher course syllabus. Edited by MAGiamberardino. IASP Press,Seattle, pp. 403–411, 2002.

35. Gebhart GF: Pathobiology of visceral pain:Molecularmechanisms and therapeutic implications.IV.Visceral afferent contributions to the pathobiology of

visceral pain. Am J Physiol Gastrointest Liver Physiol278: 834–838, 2000.

36. Ji RR, Kohno T, Moore KA, Woolf CJ: Centralsensitization and LTP: Do pain and memory share sim-ilar mechanisms? Trends Neurosci 26: 696–705, 2003.

37. Giamberardino MA, Dalal A, Valente R, VecchietL: Changes in activity of spinalcellswith muscular inputin rats with referred muscular hyperalgesia from ureteralcalculosis. Neurosci Lett 203: 89–92, 1996.

38. Malykhina AP: Neural mechanisms of pelvic or-gan cross-sensitization. Neuroscience 149: 660–672,2007.

39. Winnard KP, Dmitrieva N, Berkley KJ: Cross-organ interactions between reproductive, gastrointesti-

nal, and urinary tracts: Modulation by estrous stage andinvolvement of the hypogastric nerve. Am J PhysiolRegul Integr Comp Physiol 291: R1592–R1601, 2006.

40. Willis WD, Jr: Dorsal root potentials and dorsalroot reflexes: A double-edged sword. Exp Brain Res124: 395–421, 1999.

41. Aloisi A, Ceccarelli I, Affaitati G, Lerza R,Vecchiet L, Lapenna D, Giamberardino MA: c-Fos ex-pression in the spinal cord of female rats with artificialureteric calculosis. Neurosci Lett 361: 212–215, 2004.

42. Giamberardino MA, Affaitati G, Lerza R, FanoG, Fulle S, Belia S, Lapenna D, Vecchiet L: Evaluationof indices of skeletal muscle contraction in areas of referred hyperalgesia from an artificial ureteric stone inrats. Neurosci Lett 338: 213–216, 2003.

43. Procacci P, Francini F, Zoppi M, Maresca M:Cutaneous pain threshold changes after sympatheticblock in reflex dystrophies. Pain 1: 167–175, 1975.

44. Gibson SJ: Pain and aging: The pain experienceover the adult life span. Proceedings of the 10th WorldCongress on Pain, Progress in Pain Research and Man-agement. Edited by JO Dostrovsky, DB Carr, M Koltzen-burg, IASP Press, Seattle, 2003, pp. 767–790.

45. Stern S, Behar S, Gottlieb S: Cardiology patientpages. Aging and diseases of the heart. Circulation 108:e99–e101, 2003.

46. Wroblewski M, Mikulowski P: Peritonitis in geri-atric inpatients. Age Ageing 20: 90–94, 1991.

47. Caraceni A, Portenoy RK: An international sur-vey of cancer pain characteristics and syndromes, IASPTask Force on Cancer Pain. Pain 82: 263–274, 1999.

48. Moore AR, Clinch D: Underlying mechanisms of impaired visceral pain perception in older people. J AmGeriatr Soc 52: 132–136, 2004.

49. Viggiano A, Zagaria N, Passavanti MB,Pace MC,Paladini A, Aurilio C, Tedesco MA, Natale F, CalabroR, Monda M, De Luca E: New and low-cost auto-algometry for screening hypertension-associated hy-poalgesia. Pain Pract 9: 260–265, 2009.

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