Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region

There is evidence that the neurokinin substance P plays a role in neural mechanisms governing learning and reinforcement. Reinforcing and memory-promoting effects of substance P were found after it was injected into several parts of the brain and intraperitoneally. With regard to the close link between anxiety and memory processes for negative reinforcement learning, the aim of the present study was to gauge the effect of substance P on anxiety-related behaviors in the rat elevated plus-maze and social interaction test. Substance P was tested at injection sites where the neurokinin has been shown to promote learning and to serve as a reinforcer, namely in the periphery (after i.p. administration) and after injection into the nucleus basalis magnocellularis region. When administered i.p., substance P had a biphasic dose-response effect on behavior in the plus-maze with an anxiolytic-like action at 50 microg/kg and an anxiogenic-like one at 500 microg/kg. After unilateral microinjection into the nucleus basalis magnocellularis region, substance P (1 ng) was found to exert anxiolytic-like effects, because substance P-treated rats spent more time on the open arms of the plus-maze and showed an increase in time spent in social interaction. Furthermore, the anxiolytic effects of intrabasalis substance P were sequence-specific since injection of a compound with the inverse amino acid sequence of substance P (0.1 to 100 ng) did not influence anxiety parameters. These results show that substance P has anxiolytic-like properties in addition to its known promnestic and reinforcing effects, supporting the hypothesis of a close relationship between anxiety, memory and reinforcement processes.     

Role of substance P in pressor response of central amygdaloid nucleus to glutamate

Substance P (SP)-immunoreactive cells and the axon terminals are widely distributed in the central amygdaloid nucleus (AC) and its important projection areas. The present study showed that (1) Excitation of the AC by glutamate (Glu) or injection of SP into the AC projection areas: locus coeruleus (LC), nucleus parabrachialis (NPB), periaqueductal gray matter (PAG) or lateral hypothalamus-perifornical region (LH/PF), all elicited pressor response. (2) Preinjection of DPDPDT (a SP antagonist) into bilateral LC, NPB, PAG or LH/PF could attenuate the AC pressor response to Glu. (3) Intra-RVLM (rostral ventrolateral medulla) preinjection of either phentolamine, propranolol or atropine (but not GDEE, a Glu antagonist) could also reduce the AC pressor response. Taken together with our previous findings that the alpha-, beta-, M-receptors in RVLM mediated the pressor response to LC excitation, alpha-receptors mediated the NPB pressor response, alpha- and beta-receptors mediated the PAG pressor response; these results indicate that the SPergic projections of the AC not only directly act upon the brainstem pressor areas (LC, NPB, PAG)-RVLM system, but also indirectly via the LH/PF act upon the brainstem pressor areas-RVLM system to induce the pressor response.     

Subcompartmental organization of the ventral (protrusor) compartment in the hypoglossal nucleus of the rat

The extent and myotopic organization of the ventral (protrusor) compartment of the hypoglossal nucleus (nXII) in the rat is controversial. Of particular concern is the location of motoneurons that innervate the intrinsic (verticalis, transversus) as compared to extrinsic (genioglossus) tongue protrusor muscles. These issues were investigated with retrograde transport, lesion/degeneration/immunocytochemical, and classic Golgi staining techniques. Results from these experiments demonstrate the following: (1) the ventral compartment extends the entire rostrocaudal length of nXII and is organized into three longitudinally oriented subcompartments, one medial and one lateral within the boundaries of nXII, and one outside the confines of nXII, defined as the lateral accessory subcompartment; 2) the medial and lateral subcompartments contain motoneurons that innervate the intrinsic (verticalis, transversus) and extrinsic (genioglossus) tongue protrusor muscles, respectively, while the lateral accessory subcompartment innervates the geniohyoid muscle; (3) ventral subcompartments are unequal in size and vary along the rostrocaudal dimension of nXII. The medial subcompartment is largest caudally and smallest rostrally, while the converse is true for the lateral subcompartment. By contrast, the lateral accessory subcompartment is present only along the caudal one-half of nXII; (4) medial and lateral subcompartments are further organized into smaller subgroups. Medial and centromedial subgroups are discernible within the medial subcompartment, lateral and centrolateral subgroups within the lateral subcompartment. Both medial and lateral subgroups extend throughout the rostrocaudal length of nXII, whereas the centromedial and centrolateral subgroups are present only along the middle two-thirds of nXII where they form a central motoneuron band; (5) there is an inverse myotopic organization within the medial and lateral subcompartments such that proximal and distal portions of intrinsic and extrinsic protrusor muscles receive innervation from rostral and caudal motoneurons, respectively; and (6) there is a correlation between motoneuron morphology (size, shape and dendritic field domains), subcompartment localization, and myotopic specificity. Motoneurons in the medial subcompartment are small (mean = 23.08 microns), round to globular, with dendrites oriented medially, dorsomedially, dorsolaterally, and caudally, whereas lateral subcompartment motoneurons are large (mean = 29.49 microns), round to triangular, with dendrites directed mainly mediolaterally and dorsally. These data are relevant to understanding the functional organization of nXII and the motor control of the tongue. Results are further discussed relative to the convergence of multifunctional afferent systems in the ventromedial subcompartment of nXII.     

Functional characterization of caudal hypoglossal neurons by spectral patterns of neuronal discharges in the rat

This study evaluated the spectral characteristics of neuronal discharges in the caudal hypoglossal nucleus and their physiological relevance in adult, male Sprague Dawley rats which were anaesthetized and maintained with pentobarbital sodium. Based on auto-spectral analysis of extracellular single-neuron activity, three spectral patterns were identified in the spontaneous discharges of hypoglossal neurons. Neurons that exhibited a rhythmic pattern manifested a concentrated peak in the auto-spectrogram that corresponded to the mean discharge rate. A majority of hypoglossal neurons displayed the modulated pattern, which was manifested either as scattered power densities (wide-band modulated pattern) or with a peak frequency component that was different from the mean discharge rate (narrow-band modulated pattern). Neurons that exhibited a mixed pattern displayed both rhythmic and modulated spectral patterns. Cross-spectral analysis further revealed that respiratory modulation constituted a major physiological influence on caudal hypoglossal neurons. The respiratory modulated pattern, however, could be converted to a mixed pattern in the presence of a central dipsogen, angiotensin III. The results suggest that the spectral patterns of neuronal discharges in caudal hypoglossal neurons represent manifestations of multiple physiological information, including that regarding respiration and dipsogenesis, which is encoded in these neurons. It was also shown that this information may only be revealed by auto-spectral and cross-spectral analysis of neuronal discharge signals.     

Localization of substance P and leucine enkephalin in the nerve terminals of the guinea pig paracervical ganglion

Immunoreactivities (IR) of substance P and leucine enkephalin have been demonstrated in the guinea-pig paracervical ganglion by an immunogold electron microscope method. Both substance P-IR and leucine enkephalin-IR were detected in large synaptic vesicles with electron-dense cores. The former neuropeptide was detected in nerve terminals and varicosities comprised mainly of large vesicles with electron-dense cores; the latter was detected in nerve terminals and varicosities that also included small, clear synaptic vesicles. In a minority of nerve terminals and varicosities coexistence of both immunoreactivities could be demonstrated within vesicles with an electron-dense core. Also present in these nerve terminals and varicosities were small, clear synaptic vesicles, though these were unreactive.     

Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods

The dorsal raphe nucleus through its extensive efferents has been implicated in a great variety of physiological and behavioural functions. However, little is know about its afferents. Therefore, to identify the systems likely to influence the activity of serotonergic neurons of the dorsal raphe nucleus, we re-examined the forebrain afferents to the dorsal raphe nucleus using cholera toxin b subunit and Phaseolus vulgaris-leucoagglutinin as retrograde or anterograde tracers. With small cholera toxin b subunit injection sites, we further determined the specific afferents to the ventral and dorsal parts of the central dorsal raphe nucleus, the rostral dorsal raphe nucleus and the lateral wings. In agreement with previous studies, we observed a large number of retrogradely-labelled cells in the lateral habenula following injections in all subdivisions of the dorsal raphe nucleus. In addition, depending on the subdivision of the dorsal raphe nucleus injected, we observed a small to large number of retrogradely-labelled cells in the orbital, cingulate, infralimbic, dorsal peduncular, and insular cortice, a moderate or substantial number in the ventral pallidum and a small to substantial number in the claustrum. In addition, we observed a substantial to large number of cells in the medial and lateral preoptic areas and the medial preoptic nucleus after cholera toxin b subunit injections in the dorsal raphe nucleus excepting for those located in the ventral part of the central dorsal raphe nucleus, after which we found a moderate number of retrogradely-labelled cells. Following cholera toxin b subunit injections in the dorsal part of the central dorsal raphe nucleus, a large number of retrogradely-labelled cells was seen in the lateral, ventral and medial parts of the bed nucleus of the stria terminalis whereas only a small to moderate number was visualized after injections in the other dorsal raphe nucleus subdivisions. In addition, respectively, a substantial and a moderate number of retrogradely-labelled cells was distributed in the zona incerta and the subincertal nucleus following all tracer injections in the dorsal raphe nucleus. A large number of retrogradely-labelled cells was also visualized in the lateral, dorsal and posterior hypothalamic areas and the perifornical nucleus after cholera toxin b subunit injections in the dorsal part of the central raphe nucleus and to a lesser extent following injections in the other subdivisions. We further observed a substantial to large number of retrogradely-labelled cells in the tuber cinereum and the medial tuberal nucleus following cholera toxin b subunit injections in the dorsal part of the central dorsal raphe nucleus or the lateral wings and a small to moderate number after injections in the two other dorsal raphe nucleus subdivisions. A moderate or substantial number of labelled cells was also seen in the ventromedial hypothalamic area and the arcuate nucleus following cholera toxin injections in the dorsal part of the central dorsal raphe nucleus and the lateral wings and an occasional or small number with injection sites located in the other subdivisions. Finally, we observed, respectively, a moderate and a substantial number of retrogradely-labelled cells in the central nucleus of the amygdala following tracer injections in the ventral or dorsal parts of the central dorsal raphe nucleus and a small number after injections in the other subnuclei. In agreement with these retrograde data, we visualized anterogradely-labelled fibres heterogeneously distributed in the dorsal raphe nucleus following Phaseolus vulgaris-leucoagglutinin injections in the lateral orbital or infralimbic cortice, the lateral preoptic area, the perifornical nucleus, the lateral or posterior hypothalamic areas, the zona incerta, the subincertal nucleus or the medial tuberal nucleus. (ABSTRACT TRUNCATED)     

Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine

In the present study, we examined the effects of dopamine (DA) receptor antagonists infused into the nucleus accumbens septi (NAS) on analgesia induced by intra-ventral tegmental area (VTA) infusions of the substance P (SP) analog, DiMe-C7 or morphine and intra-NAS infusions of amphetamine. Rats received intra-NAS infusions of either the mixed DA receptor antagonist flupenthixol (1.5 or 3.0 microg/0.5 microl/side; DiMe-C7 only), the DA D1/D5 receptor antagonist SCH 23390 (0.1 microg/0.5 microl/side; DiMe-C7 only) or the DA D2-type receptor antagonist raclopride (1.0, 3.0 or 5.0 microg/0.5 microl/side). Ten minutes later, rats received intra-VTA infusions of DiMe-C7 (3.0 microg/0.5 microl/side) or morphine (3.0 microg/0.5 microl/side) or intra-NAS infusions of amphetamine (2.5 microg/0.5 microl/side). Animals were then administered the formalin test for tonic pain. Intra-NAS raclopride prevented analgesia induced by intra-VTA DiMe-C7, intra-VTA morphine and intra-NAS amphetamine. Similarly, intra-NAS flupenthixol or SCH 23390 attenuated the analgesia induced by intra-VTA DiMe-C7. These findings suggest that tonic pain is inhibited, at least in part, by enhanced DA released from terminals of mesolimbic neurons. Furthermore, the evidence that SP and opioids in the VTA mediate stress-induced analgesia suggests that the pain-suppression system involving the activation of mesolimbic DA neurons is naturally triggered by exposure to stress, pain or both.     

kappa-opioid regulation of neuronal activity in the rat supraoptic nucleus in vivo

We investigated the influence of endogenous kappa-opioids on the activity of supraoptic neurons in vivo. Administration of the kappa-antagonist nor-binaltorphimine (200 micrograms/kg, i.v.), increased the activity of phasic (vasopressin), but not continuously active (oxytocin), supraoptic neurons by increasing burst duration (by 69 +/- 24%) and decreasing the interburst interval (by 19 +/- 11%). Similarly, retrodialysis of nor-binaltorphimine onto the supraoptic nucleus increased the burst duration (119 +/- 57% increase) of vasopressin cells but did not alter the firing rate of oxytocin cells (4 +/- 8% decrease). Thus, an endogenous kappa-agonist modulates vasopressin cell activity by an action within the supraoptic nucleus. To eliminate kappa-agonist actions within the supraoptic nucleus, we infused the kappa-agonist U50,488H (2.5 micrograms/hr at 0.5 micrograms/hr) into one supraoptic nucleus over 5 d to locally downregulate kappa-receptor function. Such infusions reduced the spontaneous activity of vasopressin but not oxytocin cells and reduced the proportion of cells displaying spontaneous phasic activity from 26% in vehicle-infused nuclei to 3% in U50, 488H-infused nuclei; this treatment also prevented acute inhibition of both vasopressin and oxytocin cells by U50,488H (1000 micrograms/kg, i.v.), confirming functional kappa-receptor downregulation. In U50, 488H-infused supraoptic nuclei, vasopressin cell firing rate was increased by nor-binaltorphimine (100 and 200 micrograms/kg, i.v.) but not to beyond that found in vehicle-treated nuclei, indicating that these cells were not U50,488H-dependent. Thus, normally functioning kappa-opioid mechanisms on vasopressin cells are essential for the expression of phasic firing.     

Vulnerability to aging in the rat serotonergic system

Distributional changes of serotonergic fibers associated with aging were demonstrated immunohistochemically. Old rat brains were morphologically characterized by the presence of peculiar features of serotonergic fibers not found in the young adult brain. In 24-month-old rats, these aberrant serotonergic fibers were subdivided into two groups according to morphological alterations: type 1 fibers consisting of thin fibers with moderately enlarged varicosities, and type 2 fibers consisting of much thicker fibers that have even larger varicosities and a tortuous course. These two types of fibers were distributed differentially in the forebrain. Type 1 fibers were found mainly in the striatum and frontoparietal cortex, whereas type 2 fibers were found in the posterior cingulate cortex and dentate gyrus of the hippocampal formation. Both types of aberrant fibers were seen in amygdala, frontoparietal cortex, hypothalamus, and thalamus. In 36-month-old rats, more highly degenerating arborizations were detected, and these aberrant ramifications were classified as follows based on shape as: type 3 fibers consisting of highly arborized thin fibers with a larger number of larger varicosities, and type 4 fibers consisting of thick fibers with abundant larger varicosities. Distributional difference indicated that type 1 fibers progress into type 3 fibers, whereas type 2 develop into type 4 fibers. These findings suggest the possibility that one set of pathological fibers emanate from the dorsal raphe nucleus and the other from the median raphe. Moreover, both two sets of serotonergic fibers show age-related aberrations in their morphology over same time course.     

Regional distribution of substance P in the brain of the rat

Using a sensitive radioimmunoassay we have studied the regional distribution of substance P. The level of substance P is higher in the mesencephalon, hypothalamus and preoptic area than in other regions of the brain. Substance P is found in especially high concentrations in the reticular part of the substantia nigra and the interpeduncular nucleus. It is present in large amounts in several septal, preoptic and hypothalamic nuclei as well.     

Organization of motoneurons in the dorsal hypoglossal nucleus that innervate the retrusor muscles of the tongue in the rat

This anatomical investigation was prompted by the incomplete knowledge of the myotopic organization of the dorsal subdivison of the hypoglossal nucleus. Intrinsic muscle motoneurons were not segregated and labeled previously with regard to the lateral division of the hypoglossal nerve. Also, motoneuron number and cell size, in relation to the individual retrusor tongue musculature, were rarely addressed previously. Retrograde labeling ofretrusor muscle motoneurons in the dorsal subdivision of the rat hypoglossal nucleus was done. Cholera toxin conjugate horseradish peroxidase (CTHRP) was injected into the retrusor tongue muscles with only the lateral division of the hypoglossal nerve intact. The dorsal subdivision of the hypoglossal nucleus contained approximately 800 motoneurons ranging in cell body size from 19 to 41 microm. When either the styloglossus, hyoglossus, superior longitudinal, or inferior longitudinal muscle was isolated and injected with CTHRP, a separate motoneuron pool for each muscle was seen. The extrinsic muscle motoneurons, styloglossus and hyoglossus, were found rostrolateral and caudolateral respectively. In contrast, the intrinsic superior and inferior longitudinal muscle motoneurons were found more central and medial in the nucleus. Extrinsic muscle motoneurons were larger (approximately 30 microm) than intrinsic muscle motoneurons (approximately 26 microm; P < .0001). Intrinsic muscle motoneurons account for a great majority of the motoneurons in the dorsal aspect of the hypoglossal nucleus and their axons have been shown to be contained in the lateral (retrusor) division of the hypoglossal nerve. This study revealed the myotopic organization of the retrusor subdivision of the rat hypoglossal nucleus.     

Expression of glutamate receptor subunit 1 and nitric oxide synthase in the hypoglossal nucleus and dorsal vagal nucleus in the rat after neurectomy

Using nitric oxide synthase (NOS) and glutamate receptor subunit 1 (GluR1) immunohistochemistry, the present study demonstrated changes in the expression of NOS and GluR1 in the hypoglossal (HN) and dorsal vagal nucleus (DVN) after neurectomy. Two and 7 days after sectioning the left hypoglossal nerve, NOS expression was seen in a few neurons but GluR1 immunoreactivity was drastically reduced in the ipsilateral HN. The upregulation of NOS immunoreactivity in the HN appeared to peak at 14 days postoperation (dpo). At this period, however, the GluR1 immunoreactivity almost completely disappeared. Twenty-one, 35 and 56 days after neurectomy, NOS immunoreactivity was still expressed in the ipsilateral HN; at the same time, GluR1 immunoreactivity reappeared in a few neurons of the nucleus. Ninety days after operation, NOS immunoreactivity completely disappeared on the operated side of the nucleus, but GluR1 immunoreactivity was re-expressed in many hypoglossal neurons. The number of such neurons was obviously less than that on the unoperated side. After sectioning the left vagus nerve in the same animals, the expression of NOS immunoreactivity in the ipsilateral DVN resembled that in the HN. On the unoperated side, NOS immunoreactivity was demonstrated in some neurons in the DVN, like that in the normal. In both normal and operated rats, only a few neurons expressed GluR1 immunoreactive products on both the operated and unoperated sides of the DVN. Combining with previous results on protein synthesis observed at 14 dpo, the present investigation suggested that in the early stages after neurectomy, the expression of NOS immunoreactivity and loss of GluR1 expression in the HN may indicate the organism's double protective mechanism. Lastly, the reappearance of GluR1 in the same nucleus from 21 to 90 days after operation may reflect functional recovery of the hypoglossal neurons.     

Effect of substance P on proximal tubular reabsorption in the rat

Micropuncture and clearance techniques were used simultaneously to determine the effect of substance P on proximal tubular and overall renal function in anesthetized rats. This polypeptide, infused in saline at 50 pg/min into the abdominal aorta above the renal arteries, produced increases in urine flow, 2.7-3.7 mul/min.g kidney wt (P is less than 0.005); urinary sodium concentration, 32-61 meq/liter (P is less than 0.01); and sodium excretion, 89-223 neq/min (P is less than 0.005). Tubular fluid to plasma inulin concentration ratio measured in the last accessible proximal convolution fell from 2.21 to 1.80 (P is less than 0.001), and thus fractional reabsorption was reduced from 54 to 44% (P is less than 0.001). Absolute reabsorption by the proximal convoluted tubule was also reduced 15.5-12.5 nl/min (P is less than 0.025). In a control series of animals, saline alone infused at the same rate did not produce any statistically significant changes in the measured parameters over the same time period. The intrerenal mechanism responsible for the reduction in proximal reabsorption appears to be a tubular one since no consistent or significant changes were observed in kidney or single nephron glomerular filtration rate, renal plasma flow, or intrarenal hydrostatic pressures. No evidence was found to indicate redistribution of filtration rate, or plasma flow, or a reduction in filtration fraction.     

Alteration of serotonergic innervation in the suprachiasmatic nucleus of the rat following removal of input fibers from retina and lateral geniculate nucleus

We report the results of sclerotherapy in 20 patients with bleeding gastric varices due to hepatic schistosomiasis. In an endemic area, patients with hepatic schistosomiasis, and bleeding gastric varices seen on endoscopy to be inferior extension of esophageal varices, were treated with emergency endoscopic injection just proximal to the cardia. Hemostasis was achieved in 17. Obliteration of varices was achieved in all patients with sclerotherapy, combined with surgery. Thirteen patients who had not been operated on in the past and consented to surgery underwent esophagogastric devascularization with splenectomy. Surgery was carried out as an emergency in the three patients who did not respond to sclerotherapy and electively in 10 patients after control of bleeding. After surgery, sclerotherapy was required for remnant varices. One patient with Child-Pugh grade C cirrhosis died of hepatic encephalopathy after control of the bleed. During a median follow-up of 9 months (range, 1-25 months), recurrence of bleeding in one patient and recurrent varices in two others were controlled with sclerotherapy. One patient had a fatal hemorrhage at home. We conclude that sclerotherapy effectively controls acutely bleeding type 1 gastric varices. Combined with esophagogastric devascularization and splenectomy, long-term results may be encouraging in patients with hepatic schistosomiasis.     

Spinal projections to the parabrachial nucleus are substance P-immunoreactive

Substance P plays an important role in nociceptive processing in the spinal cord. Substance P is also present in several supraspinal regions, such as the pontine parabrachial nucleus, a major relay for autonomic regulation. In this study we examined in the cat with an immunogold method the presence of substance P-like immunoreactivity in spinoparabrachial terminals that were labelled by anterograde transport of unconjugated and lectin-conjugated horseradish peroxidase. We found that dense core vesicles in anterogradely labelled terminals were substance P-immunoreactive. Taken together with previous observations that noxious stimuli increase preprotachykinin expression in ascending nociceptive pathways from the spinal dorsal horn, the present finding provides evidence that substance P is involved in nociceptive processing also in the brain stem.     

Direct evidence for nitric oxide synthase in vagal afferents to the nucleus tractus solitarii

The anatomical relationship between vagal afferents and brain nitric oxide synthase containing terminals in the nucleus tractus solitarii was studied by means of anterograde tracing combined with immunocytochemistry and immuno-electron microscopy. Biotinylated dextran amine was injected into the nodose ganglion with a glass micropipette. Four to eight days following the injection, regions of the nucleus tractus solitarii containing biotinylated dextran amine-labelled vagal afferents and those containing nitric oxide synthase-immunopositive terminals were congruent. Many neurons exhibiting nitric oxide synthase immunoreactivity were found within the biotinylated dextran amine-containing terminal field. However dense labeling of terminals with biotinylated dextran amine precluded determination if the terminals were nitric oxide synthase-immunoreactive. Therefore, we combined degeneration of vagal afferents after removal of one nodose ganglion with nitric oxide synthase immuno-electron microscopy. Axon terminals that possessed characteristic vesicle clusters and were partially or completely engulfed by glial processes were identified as degenerating vagal afferents. Degenerating axon terminals comprised 38% of the total axon terminals in the nucleus tractus solitarii in a sample of sections; and of the degenerating axon terminals, 67% were nitric oxide synthase-immunoreactive. Nitric oxide synthase immunoreactivity was present in 41% of the non-degenerating axon terminals. Prominent staining of dendrites for nitric oxide synthase immunoreactivity indicated that much of the nitric oxide synthase in the nucleus tractus solitarii is not derived from peripheral afferents. Of the total number of dendritic profiles sampled, half were nitric oxide synthase-immunoreactive. Our data support the hypothesis that nitric oxide or nitric oxide donors may be present in primary vagal afferents that terminate in the nucleus tractus solitarii. While this study confirms that vagal afferents contain brain nitric oxide synthase, it demonstrates for the first time that the majority of nitric oxide synthase immunoreactivity in the nucleus tractus solitarii is found in intrinsic structures in the nucleus. In addition, our data show that second or higher order neurons in the nucleus tractus solitarii may be nitroxidergic and receive both nitroxidergic and non-nitroxidergic vagal input.     

The effect of substance P on collagen concentration in rat colon

Anastomotic leakage is the main reason of high mortality in colorectal surgery. The healing of anastomosis is predominantly derived from collagen fibrils. Substance P causes the proliferation of fibroblasts and connective tissue. The effect of SP on postoperative changes of collagen concentration was measured around the anastomotic side in rats. The studies shows, that SP induces a significant decrease in collagen synthesis in colon.