Abstract
The evoked expression of the immediate early gene encoded proteins c-Fos and Krox-24 was used to study activation of hindbrain neurons as a function of the development of Cyclophosphamide (CP) cystitis in behaving rats. CP-injected animals received a single dose of 100 mg/kg i.p. under transient volatile anesthesia and survived for 1 to 4 h in order to cover the whole postinjection period during which the disease develops. CP-injected groups included: (1) animals with minor simple chorionic edema, an early characteristic of inflammation (1 h postinjection); (2) animals with well developed simple chorionic edema (2 h postinjection); (3) animals with mild inflammation (chorionic edema accompanied by epithelial cleavage; 3 h postinjection); and (4) animals with complete inflammation (4 h postinjection). In addition to onset of chorionic edema, the earliest postinjection period also included the general aspects of the nervous reaction consecutive to the injection process (handling, transient volatile anesthesia and postanesthesia awakening, abdominal pinprick, CP blood circulating effects). Controls included both noninjected animals and saline injected animals surviving for the same times as CP injected ones. Quantitative results come from c-Fos expression. It has been shown that: (1) saline injection is a significant stimulus for only nucleus O and central gray pars alpha and nucleus medialis of the dorsal vagal complex; (2) all structures driven by CP injection (nucleus O and central gray pars alpha, locus coeruleus, Barrington's nucleus and parabrachial area mostly in its ventral and lateral subdivisions, dorsal vagal complex, ventrocaudal portion of lateral bulbar reticular formation) responded vigorously shortly after injection, but only two (dorsal vagal complex, ventrocaudal portion of lateral bulbar reticular formation) showed increased or renewed activity when cystitis completely developed, i.e., when noxious visceral inputs reached highest levels. Regarding the sequential activation of these structures in relation to postinjection time, evidence is given that: (1) a large variety of hindbrain structures are differentially involved in either the general reaction consecutive to the injection process or to various degrees of cystitis; (2) these structures extend from the brain spinal cord to the pons mesencephalon transitional junction levels; (3) the two structures most powerfully driven by visceronociceptive inputs are also the most caudal ones, being located at the brain spinal cord junction level; and (4) the dorsal vagal complex could be the main hindbrain visceral pain center, with three particular subdivisions, the nucleus medialis, nucleus commissuralis, and ventralmost part of area postrema, being involved.
Similar content being viewed by others
References
Abelli L, Conte B, Somma V, Maggi CA, Giuliani S, Meli A (1989) A method for studying pain arising from the urinary bladder in conscious, freely moving rats. J Urology 141:148–151
Altschuler SM, Ferenci DA, Lynn RB, Miselis RR (1991) Representation of the cecum in the lateral dorsal motor nucleus of the vagus nerve and commissural subnucleus of the nucleus tractus solitarii in rat. J Comp Neurol 304:261–274
Anton F, Herdegen T, Peppel P, Leah JD (1991) c-Fos-like immu noreactivity in rat brainstem neurons following noxious chemical stimulation of the nasal mucosa. Neuroscience 41:629–641
Berkley KJ, Wood E, Scofield SL, Little M (1995) Behavioral responses to uterine or vaginal distension in the rat. Pain 61:121–131
Bernstein IL (1978) Learned taste aversions in children receiving chemotherapy. Science 200:1302–1303
Birder LA, Groat W de (1992) Increased c-fos expression in spinal neurons after irritation of the lower urinary tract in the rat. J Neurosci 12:4878–4889
Bon K, Lantéri-Minet M, Pommery J de, Menétrey D (1994) Spinal and hindbrain areas involved in visceronociception related to cyclophosphamide cystitis as revealed by the expression of c-Fos protein (abstract). Eur J Neurosci [Suppl] 7:31
Bonaz B, Taché Y (1994) Water-avoidance stress induced c-fos expression in the rat brain and stimulation of fecal output: role of corticotropin releasing factor. Brain Res 641:21–28
Brady LS, Lynn AB, Herkenham M, Gottesfeld Z (1994) Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain. J Neurosci 14:4951–4964
Bravo R (1990) Growth factor inducible genes in fibroblasts. In: Habencht A (eds) Growth factors, differenciation factors and cytokines. Springer, Berlin Heidelberg New York, pp 324–343
Brock N, Gross R, Hohorst HJ, Klein HO, Schneider B (1971) Activation of cyclophosphamide in man and animals. Cancer 27:1512–1529
Brock N, Pohl J, Stekar J (1981) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention. I. Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer 17:595–607
Bullitt E (1990) Expression of c-Fos like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol 296:517–530
Ceccatelli S, Villar MJ, Goldstein M, Hökfelt T (1989) Expression of c-Fos immunoreactivity in transmitter characterized neurons after stress. Proc Natl Acad Sci USA 86:9569–9573
Chan RKW, Brown ER, Ericsson A, Kovács KJ, Sawchenko PE (1993) A comparison of two immediate early genes, c-fos and NGFI-B, as markers for functional activation in stress related neuroendocrine circuitry. J Neurosci 13:5126–5138
Chan RKW, Sawchenko PE (1994) Spatially and temporally differentiated patterns of c-fos expression in brainstem catechol aminergic cell groups induced by cardiovascular challenges in the rat. J Comp Neurol 348:433–460
Chen X, Herbert J (1995) Regional changes in c-fos expression in the basal forebrain and brainstem during adaptation to repeated stress: correlations with cardiovascular, hypothermic and endocrine responses. Neuroscience 64:675–685
Ciriello J, Caverson MM, Polosa C (1986) Function of the ventro lateral medulla in the control of the circulation. Brain Res Brain Res Rev 11:359–391
Cox PJ (1979) Cyclophosphamide cystitis — identification of acrolein as the causative agent. Biochem Pharmacol 28:2045–2049
Craig AD (1992) Spinal and trigeminal lamina I input to the locus coeruleus anterogradely labeled with Phaseolus vulgaris leucoagglutinin (PHA-L) in the cat and the monkey. Brain Res 584:325–328
Cullinan WE, Herman JP, Battaglia DF, Akil H, Watson SJ (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience 64:477–505
Cunningham ET Jr, Miselis RR, Sawchenko PE (1994) The relationship of efferent projections from the area postrema to vagal motor and brain stem catecholamine containing cell groups: an axonal transport and immunohistochemical study in the rat. Neuroscience 58:635–648
Cutrera RA, Kalsbeek A, Pévet P (1993) No triazolam induced expression of Fos protein in raphe nuclei of the male Syrian hamster. Brain Res 602:14–20
Dampney RAL (1994) The subretrofacial vasomotor nucleus: anatomical, chemical and pharmacological properties and role in cardiovascular regulation. Prog Neurobiol 42:197–227
Esteves F, Lima D, Coimbra A (1993) Structural types of spinal cord marginal (lamina-I) neurons projecting to the nucleus of the tractus solitarius in the rat. Somatosens Mot Res 10:203–216
Ferguson AV (1991) The area postrema: a cardiovascular control centre at the blood brain interface? Can J Physiol Pharmacol 69:1026–1034
Fulwiler CE, Saper CB (1984) Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res Brain Res Rev 7:229–259
Gass P, Herdegen T, Bravo R, Kiessling M (1993) Induction and suppression of immediate early genes in specific rat brain regions by the non competitive N-methyl-d-aspartate receptor antagonist MK-801. Neuroscience 53:749–758
Grant SJ, Bittman K, Benno RH (1992) Both phasic sensory stimulation and tonic pharmacological activation increase fos like immunoreactivity in the rat locus coeruleus. Synapse 12:112–118
Gross PM, Wall KM, Wainman DS, Shaver SW (1991) Subregional topography of capillaries in the dorsal vagal complex of rats. II. Physiological properties. J Comp Neurol 306:83–94
Hammond DL, Presley R, Gogas KR, Basbaum AI (1992) Morphine or U-50,488 suppresses Fos protein-like immunoreactivity in the spinal cord and nucleus tractus solitarii evoked by a noxious visceral stimulus in the rat. J Comp Neurol 315:244–253
Herbert H, Moga MM, Saper CB (1990) Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 293:540–580
Herdegen T, Kovary K, Leah J, Bravo R (1991) Specific temporal and spatial distribution of JUN, FOS, KROX-24 proteins in spinal neurons following noxious transynaptic stimulation. J Comp Neurol 313:178–191
Hochstenbach SL, Solano-Flores LP, Ciriello J (1993) Fos induction in brainstem neurons by intravenous hypertonic saline in the conscious rat. Neurosci Lett 158:225–228
Houpt TA, Philopena JM, Wessel TC, Joh TH, Smith GP (1994) Increased c-fos expression in nucleus of the solitary tract correlated with conditioned taste aversion to sucrose in rats. Neurosci Lett 172:1–5
Hubscher CH, Berkley K (1994) Responses of neurons in caudal solitary nucleus of female rats to stimulation of vagina, cervix, uterine horn and colon. Brain Res 664:1–8
Hunt SP, Pini A, Evan G (1987) Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 328:632–634
Jasmin L, Wang H, Tarczy-Hornoch K, Levine JD, Basbaum AI (1994) Differential effects of morphine on noxious stimulus evoked fos like immunoreactivity in subpopulations of spino parabrachial neurons. J Neurosci 14:7252–7260
Kaufman GD, Anderson JH, Beitz AJ (1992) Fos defined activity in rat brainstem following centripetal acceleration. J Neurosci 12:4489–4500
Krukoff TL, Morton TL, Harris KH, Jhamandas JH (1992) Expression of c-fos protein in rat brain elicited by electrical stimulation of the pontine parabrachial nucleus. J Neurosci 12:3582–3590
Kuru M (1965) Nervous control of micturition. Physiol Rev 45:425–494
Lantéri-Minet M, Isnardon P, Pommery J de, Menétrey D (1993a) Spinal and hindbrain structures involved in viscero and viscer onociception as revealed by the expression of Fos, Jun and Krox-24 proteins. Neuroscience 55:737–753
Lantéri-Minet M, Pommery J de, Herdegen T, Weil-Fugazza J, Bravo R, Menétrey D (1993b) Differential time course and spatial expression of Fos, Jun and Krox-24 proteins in spinal cord of rats undergoing subacute or chronic somatic inflammation. J Comp Neurol 333:223–235
Lantéri-Minet M, Weil-Fugazza J, Pommery J de, Menétrey D (1994) Hindbrain structures involved in pain processing as revealed by the expression of c-Fos and other immediate early gene proteins. Neuroscience 58:287–298
Lantéri-Minet M, Bon K, Pommery J de, Michiels JF, Menétrey D (1995) Cyclophosphamide cystitis as a model of visceral impairment in rats: model elaboration and spinal structures involved as revealed by the expression of c-Fos and Krox-24 proteins. Exp Brain Res 105:220–232
Lee J-H, Beitz A (1993) The distribution of brainstem and spinal cord nuclei associated with frequencies of electroacupuncture analgesia. Pain 52:11–28
Li VW, Dampney RAL (1992) Expression of c-fos protein in the medulla oblongata of conscious rabbits in response to baro receptor activation. Neurosci Lett 144:70–74
Lima D, Mendes-Ribeiro JA, Coimbra A (1991) The spino-lateroreticular system of the rat: projections from the superficial dorsal horn and structural characterization of marginal neurons involved. Neuroscience 45:137–152
Lu J, Hathaway CB, Bereiter DA (1993) Adrenalectomy enhances Fos-like immunoreactivity within the spinal trigeminal nucleus induced by noxious thermal stimulation of the cornea. Neuroscience 54:809–818
Mack KJ, Mack PA (1992) Induction of transcription factors in somatosensory cortex after tactile stimulation. Mol Brain Res 12:141–147
MacMahon SB, Abel C (1987) A model for the study of visceral pain states: chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals. Pain 28:109–127
Menétrey D, Basbaum AI (1987) Spinal and trigeminal projections to the nucleus of the solitary tract: a possible substrate for somatovisceral and viscerovisceral reflex activation. J Comp Neurol 255:439–450
Menétrey D, Pommery J de (1991) Origins of spinal ascending pathways that reach central areas involved in visceroception and visceronociception in the rat. Eur J Neurosci 3:249–259
Menétrey D, Pommery J de, Baimbridge KG, Thomasset M (1992a) Calbindin-D28K (CaBP28k)like immunoreactivity in ascending projections. I. Trigeminal nucleus caudalis and dorsal vagal complex projections. Eur J Neurosci 4:61–69
Menétrey D, Pommery J de, Thomasset M, Baimbridge KG (1992b) Calbindin-D28K-like immunoreactivity in ascending projections. II. Spinal projections to brain stem and mesencephalic areas. Eur J Neurosci 4:70–76
Menétrey D, Gannon A, Levine JD, Basbaum AI (1989) Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation. J Comp Neurol 285:177–195
Menétrey D, Roudier F, Besson JM (1983) Spinal neurons reaching the lateral reticular nucleus as studied in the rat by retrograde transport of horseradish peroxidase. J Comp Neurol 220:439–452
Morgan JT, Curran T (1991) Stimulus transcription coupling in the nervous system: involvement of the inducible protooncogenes fos and jun. Annu Rev Neurosci 14:421–451
Naquet R (1993) Ethical and moral considerations in the design of experiments. Neuroscience 57:183–189
Ness TJ, Gebhart GF (1988) Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res 450:153–169
Nordling L, Liedberg H, Ekman P, Lundeberg T (1990) Influence of the nervous system on experimentally induced urethral inflammation. Neurosci Lett 115:183–188
Nozaki K, Boccalini P, Moskowitz MA (1992) Expression of c-fos like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. Neuroscience 49:669–680
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, Sydney
Philips FS, Sternberg SS, Cronin AP, Vidal PM (1961) Cyclophos phamide and urinary bladder toxicity. Cancer Res 21:1577–1589
Piechaczyk M, Blanchard JM (1994) c-Fos proto-oncogene regulation and function. Crit Rev Oncol Hematol 17:93–131
Raybould H, Gayton RJ, Dockray GJ (1985) CNS effects of circulating CCK8:involvement of brainstem neurones responding to gastric distension. Brain Res 342:187–190
Ricardo JA, Koh ET (1978) Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res 153:1–26
Riche D, Pommery J de, Menétrey D (1990) Neuropeptides and catecholamines in efferent projections of the nuclei of the solitary tract in the rat. J Comp Neurol 293:399–424
Rivest S, Torres G, Rivier C (1992) Differential effects of central and peripheral injection of interleukin-1β on brain c-fos expression and neuroendocrine functions. Bain Res 587:13–23
Rutherfurd SD, Widdop RE, Sannajust F, Louis WJ, Gundlach AL (1992) Expression of c-fos and NGFI-A messenger RNA in the medulla oblongata of the anaesthetized rat following stimulation of vagal and cardiovascular afferents. Mol Brain Res 13:301–312
Saper CB, Loewy AD (1980) Efferent connections of the parabrachial nucleus in the rat. Brain Res 197:291–317
Sawchenko PE (1983) Central connections of the sensory and motor nuclei of the vagus nerve. J. Autonom Nerv Syst 9:13–26
Senba E, Matsunaga K, Tohyama M, Noguchi K (1993) Stress-induced c-Fos expression in the rat brain: activation mechanism of sympathetic pathway. Brain Res Bull 31:329–344
Shapiro RE, Miselis RR (1985) The central neural connections of the area postrema of the rat. J Comp Neurol 234:344–364
Shaver SW, Pang JJ, Wall KM, Sposito NM (1991) Subregional topography of capillaries in the dorsal vagal complex of rats. II. Physiological properties. J Comp Neurol 306:83–94
Slugg RM, Light AR (1994) Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 339:49–61
Smith DW, Day TA (1994) c-Fos expression in hypothalamic neurosecretory and brainstem catecholamine cells following noxious somatic stimuli. Neuroscience 58:765–775
Smith OA, De Vito JL (1984) Central neural integration for the control of autonomie responses associated with emotion. Annu Rev Neurosci 7:43–65
Spyer KM (1989) Neural mechanisms involved in cardiovascular control during affective behaviour. Trends Neurosci 12:506–513
Strassman AM, Mineto Y, Vos BP (1994) Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of durai blood vessels in the rat. J Neurosci 14:3725–3735
Strassman AM, Vos BP (1993) Somatotopic and laminar organization of fos-like immunoreactivity in the medullary and upper cervical dorsal horn induced by noxious facial stimulation in the rat. J Comp Neurol 331:495–516
Tassorelli C, Joseph SA (1995) Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 682:167–181
Tavares I, Lima D, Coimbra A (1993) Neurons in the superficial dorsal horn of the rat spinal cord projecting to the medullary ventrolateral reticular formation express c-fos after noxious stimulation of the skin. Brain Res 623:278–286
Tsukamoto G, Adachi A (1994) Neural responses of rat area postrema to stimuli producing nausea. J Autonom Nerv Syst 49:55–60
Valentino RJ, Page ME, Luppi PH, Zhu Y, Van Bockstaele E, Aston-Jones G (1994) Evidence for widespread afferents to Bar rington's nucleus, a brainstem region rich in corticotropin-releasing hormone neurons. Neuroscience 62:125–143
Valentino RJ, Page ME, Van Bockstaele E, Aston-Jones G (1992) Corticotropin releasing factor innervation of the locus coeruleus region: distribution of fibers and sources of input. Neuroscience 48:689–705
Van der Kooy D, Koda LY (1983) Organization of the projections of a circumventricular organ: the area postrema in the rat. J Comp Neurol 219:328–338
Watson NA, Notley RG (1973) Urological complications of cyclo phosphamide. Br J Urol 45:606–609
Worley PF, Bhat RV, Baraban JM, Erickson CA, McNaughton BL, Barnes CA (1993) Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long term enhancement. J Neurosci 13:4776–4786
Yamada J, Kitamura T (1992) Spinal cord cells innervating the bilateral parabrachial nuclei in the rat. A retrograde fluorescent double labeling study. Neurosci Res 15:273–280
Yamamoto T, Shimura T, Sako N, Azuma S, Bai W-Zh, Wakisaka S (1992) C-fos expression in the rat brain after intraperitoneal injection of lithium chloride. Neuroreport 3:1049–1052
Zittel TT, De Giorgio R, Brecha NC, Sternini C, Raybould HE (1993) Abdominal surgery induces c-fos expression in the nucleus of the solitary tract in rat. Neurosci Lett 159:79–82
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bon, K., Lantéri-Minet, M., de Pommery, J. et al. Cyclophosphamide cystitis as a model of visceral pain in rats. A survey of hindbrain structures involved in visceroception and nociception using the expression of c-Fos and Krox-24 proteins. Exp Brain Res 108, 404–416 (1996). https://doi.org/10.1007/BF00227263
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00227263