Hypersensitivity In Adult Rats Research Articles

Towards a central origin of nociceptive hypersensitivity in adult rats after a neonatal maternal separation.

Early life adversities influence a nervous system still in development with long-term consequences for later life. These include nociceptive circuit alterations critical to shape an adaptive pain response to protect the organism from potential damage. Adult rats with a history of neonatal maternal separation (NMS) display visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anaesthetized adult rats during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat's hindpaws. This nicely explains the hypernociceptive behaviours seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e., TRPV1, TRPM8 and TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevation of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS are associated with reduced spinal cord inhibition favouring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites, as other NMS-associated symptoms include excessive anxiety and impaired sociability.

Unraveling the role of Epac1-SOCS3 signaling in the development of neonatal-CRD-induced visceral hypersensitivity in rats.

AimsVisceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti‐inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro‐inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1‐SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1‐SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin‐releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD).MethodsRats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1‐SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT‐PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology.ResultsIn neonatal‐CRD‐induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL‐6 levels elevated in PVN. However, infusion of Epac agonist 8‐pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV‐SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL‐6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI‐09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL‐6 into PVN simulated the visceral hypersensitivity.ConclusionsInactivation of Epac1‐SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.

Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice.

Early life stress (ELS) disposes to functional gastrointestinal diseases in adult, such as irritable bowel syndrome (IBS). Maternal separation (MS) is a well-known animal model of IBS and has been shown to induce visceral hypersensitivity in adult rats and mice. However, to the best of our knowledge, it has not been reported whether MS induces visceral hypersensitivity in young mice, such as the post-weaning mice. Moreover, the method for evaluation of visceral sensitivity also has not been described. Accordingly, the present study aims to evaluate the visceral sensitivity caused by MS in post-weaning mice and develop a novel and small size distention balloon for assessment of visceral sensitivity of such mice. Male pups of C57BL/6 mice were randomly divided into two groups, MS (n = 12) and non-separation (NS) (n = 10). MS pups were separated from the dams through postnatal days (PND) 2 to 14, while NS pups were undisturbed. After, all pups stayed with respective dams and were weaned at PND 22. Visceral sensitivity was evaluated by colorectal distention (CRD) with a novel and small size distention balloon at PND 25. The threshold of abdominal withdrawal reflex (AWR) scores were significantly lower in MS than NS. In addition, AWR scores at different pressures of CRD were significantly higher in MS than NS. The results demonstrate that MS induced visceral hypersensitivity in post-weaning mice. The designed small size distention balloon for evaluation of visceral sensitivity is of significance to further study the pathophysiology of IBS from early life to adulthood.

Decreased miR-325-5p Contributes to Visceral Hypersensitivity Through Post-transcriptional Upregulation of CCL2 in Rat Dorsal Root Ganglia.

Chronic visceral hypersensitivity is an important type of chronic pain with unknown etiology and pathophysiology. Recent studies have shown that epigenetic regulation plays an important role in the development of chronic pain conditions. However, the role of miRNA-325-5p in chronic visceral pain remains unknown. The present study was designed to determine the roles and mechanism of miRNA-325-5p in a rat model of chronic visceral pain. This model was induced by neonatal colonic inflammation (NCI). In adulthood, NCI led to a significant reduction in the expression of miRNA-325-5p in colon-related dorsal root ganglia (DRGs), starting to decrease at the age of 4weeks and being maintained to 8weeks. Intrathecal administration of miRNA-325-5p agomir significantly enhanced the colorectal distention (CRD) threshold in a time-dependent manner. NCI also markedly increased the expression of CCL2 (C-C motif chemokine ligand 2) in colon-related DRGs at the mRNA and protein levels relative to age-matched control rats. The expression of CXCL12, IL33, SFRS7, and LGI1 was not significantly altered in NCI rats. CCL2 was co-expressed in NeuN-positive DRG neurons but not in glutamine synthetase-positive glial cells. Furthermore, CCL2 was mainly expressed in isolectin B4-binding- and calcitonin gene-related peptide-positive DRG neurons but in few NF-200-positive cells. More importantly, CCL2 was expressed in miR-325-5p-positive DRG neurons. Intrathecal injection of miRNA-325-5p agomir remarkably reduced the upregulation of CCL2 in NCI rats. Administration of Bindarit, an inhibitor of CCL2, markedly raised the CRD threshold in NCI rats in a dose- and time-dependent manner. These data suggest that NCI suppresses miRNA-325-5p expression and enhances CCL2 expression, thus contributing to visceral hypersensitivity in adult rats.

Repeated neonatal needle-prick stimulation increases inflammatory mechanical hypersensitivity in adult rats

Background and aimsNewborn infants are vulnerable to procedural stress and pain exposure on the first weeks of life that represents a critical period for the development of nociceptive, sensory, emotional, and social functions. We evaluated the nociceptive behavior of adult male and female rats that were submitted to nociceptive experience in the neonatal period and the maternal behavior in the postnatal period. MethodsThe animals were submitted to repetitive needle pricking from the second to the fifteenth postnatal day (PND 2–15). Maternal behavior and litter weight were evaluated during this period. Mechanical sensitivity to pain was assessed in offsprings during the adulthood by exposing them to inflammatory stimuli, including formalin test or the Freund’s complete adjuvant (CFA) injection followed by the electronic von Frey test at 0, 3, 6 and 24 h later. ResultsMaternal behavior and litter weight were not altered by pinprick stimuli during PND 2–15. Additionally, pinprick stimulation reduced the paw withdrawal threshold in CFA-injected animals compared to control. In the formalin test, there was a difference between the genders. Female rats are statically more sensitive to formalin stimulation and showed an increased licking time in both the first and second phases and increased number of flinches in second phase. ConclusionsExperiencing early life repetitive pain exposure increased inflammatory pain sensitivity in adult offspring rats and female rats are more sensitive to chemical stimulation. ImplicationsFuture investigations of the mechanisms involved in this effect may contribute to the improvement of the understanding of inflammatory pain sensitivity differences.

Maternal Separation Induced Visceral Hypersensitivity from Childhood to Adulthood.

Background/AimsEarly adverse life events (EALs) are relevant to irritable bowel syndrome in adulthood. Maternal separation (MS), as one of the EALs, has proved to induce visceral hypersensitivity in adult rats. However, the effect of MS on visceral hypersensitvity from the post-weaning period to adulthood remains unknown.MethodsOne hundred and ten neonatal Sprague-Dawley rats were randomly divided into 2 groups: rats in the MS group were exposed to 3 hours daily MS on postnatal day (PND) 2–14; the normal control (NC) group remained undisturbed. Visceral sensitivity was determined by measuring the visceromotor response to colorectal distention on PND21, 35, and 56. Anxiety-like behaviors were measured by the open field test.ResultsCompared with NC rats, MS rats showed significant visceral hypersensitivity from the post-weaning period to adult. The proportion of visceral hypersensitive rats decreased with age from 87.5% to 70.0% in the female MS group and from 90.0% to 66.7% in the male MS group. The relative VMR ratio of MS and NC on PND21 was higher than PND35 and PND56. MS rats showed decreased ability of movement and exploration to the novel environment in the post-weaning period, obesity in the prepubertal period, and more anxiety-like behaviors in adulthood.ConclusionsMS can significantly affect visceral sensitivity and behaviors of rats in different age stages, especially in the post-weaning period. Visceral hypersensitivity of MS rats is more pronounced in the post-weaning period and slightly restored in adults. Thus, visceral hypersensitivity in the post-weaning period might play a more meaningful pathophysiologic role in the formation of adult irritable bowel syndrome.

Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex.

Background/AimsWistar rat dams exposed to limited nesting stress (LNS) from post-natal days (PND) 2 to 10 display erratic maternal behavior, and their pups show delayed maturation of the hypothalamic-pituitary-adrenal axis and impaired epithelial barrier at PND10 and a visceral hypersensitivity at adulthood. Little is known about the impact of early life stress on the offspring before adulthood and the influence of sex. We investigated whether male and female rats previously exposed to LNS displays at weaning altered corticosterone, intestinal permeability, and microbiota.MethodsWistar rat dams and litters were maintained from PND2 to 10 with limited nesting/bedding materials and thereafter reverted to normal housing up to weaning (PND21). Control litters had normal housing. At weaning, we monitored body weight, corticosterone plasma levels (enzyme immunoassay), in vivo intestinal to colon permeability (fluorescein isothiocyanate-dextran 4 kDa) and fecal microbiota (DNA extraction and amplification of the V4 region of the 16S ribosomal RNA gene).ResultsAt weaning, LNS pups had hypercorticosteronemia and enhanced intestinal permeability with females > males while body weights were similar. LNS decreased fecal microbial diversity and induced a distinct composition characterized by increased abundance of Gram positive cocci and reduction of fiber-degrading, butyrate-producing, and mucus-resident microbes.ConclusionsThese data indicate that chronic exposure to LNS during the first week post-natally has sustained effects monitored at weaning including hypercorticosteronemia, a leaky gut, and dysbiosis. These alterations may impact on the susceptibility to develop visceral hypersensitivity in adult rats and have relevance to the development of irritable bowel syndrome in childhood.

TRPV1-mediated presynaptic transmission in basolateral amygdala contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation.

The central mechanisms of visceral hypersensitivity remain largely unknown. It’s reported that there are highest densities of TRPV1 labeled neurons within basolateral amygdala (BLA). The aim of this study was to explore the role and mechanisms of TRPV1 in BLA in development of visceral hypersensitivity. Visceral hypersensitivity was induced by neonatal maternal deprivation (NMD) and was quantified by abdominal withdrawal reflex. Expression of TRPV1 was determined by Western blot. The synaptic transmission of neurons in BLA was recorded by patch clamping. It was found that the expression of TRPV1 in BLA was significantly upregulated in NMD rats; glutamatergic synaptic activities in BLA were increased in NMD rats; application of capsazepine (TRPV1 antagonist) decreased glutamatergic synaptic activities of BLA neurons in NMD slices through a presynaptic mechanism; application of capsaicin (TRPV1 agonist) increased glutamatergic synaptic activities of BLA neurons in control slices through presynaptic mechanism without affecting GABAergic synaptic activities; microinjecting capsazepine into BLA significantly increased colonic distension threshold both in control and NMD rats. Our data suggested that upregulation of TRPV1 in BLA contributes to visceral hypersensitivity of NMD rats through enhancing excitation of BLA, thus identifying a potential target for treatment of chronic visceral pain.

The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability.

Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.

Sensitization of sodium channels by cystathionine β‐synthetase activation in colon primary sensory neurons contributes to visceral hypersensitivity in adult rats with neonatal maternal deprivation (651.20)

Aims: This study was designed to determine roles for sodium channels and endogenous H2S signaling in a rat model of chronic visceral hypersensitivityinduced by neonatal maternal deprivation (NMD). Methods: Neonatal male rats were exposed to a 3 hour period of daily maternal separation. Colon‐specific DRG neurons were acutely dissociated for measuring excitability and sodium channel currents under whole‐cell patch clamp configurations. Expression of NaV1.8 was analyzed by western blot. Results: NMD significantly increased AWR scores. TTX‐resistant sodium current density was greatly enhanced in colon DRG neurons, activation curves showed a leftward shift in NMD rats. Furthermore, NMD remarkably enhanced expression of NaV1.8 at protein levels. AOAA, an inhibitor of CBS, significantly suppressed the expression of NaV1.8. AOAA treatment also reduced the TTX‐R sodium current density, and reversed hyperexcitability of colon‐specific DRG neurons in NMD rats. Conversely, addition of NaHS, a donor of H2S, greatly enhanced TTX‐R sodium current density, leftshifted activation curve and enhanced excitability of colon DRG neurons in age‐matched healthy rats. Conclusion: Our data suggest that NMD enhances TTX‐resistant sodium activity of colon DRG neurons, which is most likely mediated by CBS‐H2S signaling, thus contributing to chronic visceral hypersensitivity.Grant Funding Source: Supported by National Natural Science Foundation of China

Mo1861 Upregulation of Endogenous Cystathionine-β Synthase Contributes to Visceral Hypersensitivity in Adult Rats Following Neonatal Maternal Deprivation

Mo1861 Upregulation of Endogenous Cystathionine-β Synthase Contributes to Visceral Hypersensitivity in Adult Rats Following Neonatal Maternal Deprivation

Nerve growth factor‐mediated neuronal plasticity in spinal cord contributes to neonatal maternal separation‐induced visceral hypersensitivity in rats

Visceral hyperalgesia is a multifactorial gastrointestinal disorder which featured with alterations of abdominal motility and/or gut sensitivity, and is believed to be triggered by environmental stressor or psychological factors. However, its etiology remains incompletely understood. In this study, we aimed to investigate whether nerve growth factor (NGF)-mediated neuronal plasticity is involved in neonatal maternal separation (NMS)-induced visceral hypersensitivity in adult rats, and whether NGF antagonist can attenuate or block such development. In our experiments, animals subjected to NMS were developed with visceral hyperalgesia at age of 8 weeks. The threshold for visceral pain among these NMS rats was remarkably lowered than that of the normal handling (NH) rats; however, the expression levels of NGF, c-fos, calcitonin gene-related peptide (CGRP), Substance P, and tyrosine kinases A (TrkA) were notably elevated in lumbosacral spinal cord and/or dorsal root ganglion (DRG) when comparing to those of the NH rats. Further, as intra-peritoneal administration of NGF (10 μl at 1 μg/kg/day) was given to NH rats during neonatal period, effects that comparable to NMS induction were observed in the adulthood. In contrast, when NMS rats were treated with NGF antagonist K252a (10 μl/day from postnatal days 2-14), which acts against tyrosine kinases, the neonatal stress-induced down-shifted visceral pain threshold was restored and neuronal activation, specifically NGF and neuropeptide production, was attenuated. In conclusion, our data strongly suggest that NGF triggers neuronal plasticity and plays a crucial role in NMS-induced visceral hypersensitivity in which NGF antagonism provides positive inhibition via blocking the tyrosine phosphorylation of TrkA.

Upregulation of Cystathionine Beta-Synthetase Expression by Nuclear Factor-Kappa B Activation Contributes to Visceral Hypersensitivity in Adult Rats with Neonatal Maternal Deprivation

BackgroundIrritable bowel syndrome (IBS) is characterized by chronic visceral hyperalgesia (CVH) that manifested with persistent or recurrent abdominal pain and altered bowel movement. However, the pathogenesis of the CVH remains unknown. The aim of this study was to investigate roles of endogenous hydrogen sulfide (H2S) producing enzyme cystathionine beta-synthetase (CBS) and p65 nuclear factor-kappa B subunits in CVH.ResultsCVH was induced by neonatal maternal deprivation (NMD) in male rats on postnatal days 2–15 and behavioral experiments were conducted at the age of 7–15 weeks. NMD significantly increased expression of CBS in colon-innervating DRGs from the 7th to 12th week. This change in CBS express is well correlated with the time course of enhanced visceromoter responses to colorectal distention (CRD), an indicator of visceral pain. Administration of AOAA, an inhibitor of CBS, produced a dose-dependent antinociceptive effect on NMD rats while it had no effect on age-matched healthy control rats. AOAA also reversed the enhanced neuronal excitability seen in colon-innervating DRGs. Application of NaHS, a donor of H2S, increased excitability of colon-innervating DRG neurons acutely dissociated from healthy control rats. Intrathecal injection of NaHS produced an acute visceral hyperalgesia. In addition, the content of p65 in nucleus was remarkably higher in NMD rats than that in age-matched controls. Intrathecal administration of PDTC, an inhibitor of p65, markedly reduced expression of CBS and attenuated nociceptive responses to CRD.ConclusionThe present results suggested that upregulation of CBS expression, which is mediated by activation of p65, contributes to NMD-induced CVH. This pathway might be a potential target for relieving CVH in patients with IBS.

Neonatal cystitis-induced colonic hypersensitivity in adult rats: a model of viscero-visceral convergence

The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms. Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days [(postnatal (PN) days 14-16)]. The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissues. CRD- or urinary bladder distension (UBD)-sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N-methyl-d-aspartic acid (NMDA)-NR1 subunit in the lumbo-sacral (L6-S1) spinal cord was examined using Western blot. The VMR to CRD (≥10mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD-sensitive PNAs from the zymosan-treated rats was significantly higher than the saline-treated control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (P>0.05). The expression of spinal NR1 subunit was significantly higher in zymosan-treated rats compared with saline-treated rats (P<0.05). Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD-sensitive PNAs. Neonatal cystitis does result in overexpression of spinal NR1 subunit in adult rats.

S1814 Neonatal Cystitis-Induced Colonic Hypersensitivity in Adult Rats: A Model of Viscero-Visceral Convergence

S1814 Neonatal Cystitis-Induced Colonic Hypersensitivity in Adult Rats: A Model of Viscero-Visceral Convergence

Ice Water Testing Reveals Hypersensitivity in Adult Rats That Experienced Neonatal Bladder Inflammation: Implications for Painful Bladder Syndrome/Interstitial Cystitis

We determined whether clinical observations of hypersensitivity to ice water testing, that is infusion of ice-cold saline into the bladder, in patients with painful bladder syndrome/interstitial cystitis have a parallel in a rat model of bladder hypersensitivity produced by neonatal inflammation. Rat pups were anesthetized as neonates (postnatal days 14 to 16). In some pups the bladder was inflamed by intravesical zymosan treatment. As adults, the rats were re-anesthetized and tested for abdominal muscle contractions to ice water testing, measured on electromyogram. Various neonatally treated groups of rats underwent bladder re-inflammation/no re-inflammation and/or bladder distention before ice water testing. Other control rats were treated only in adulthood. Rats that underwent bladder inflammation as neonates manifested bladder hypersensitivity in adulthood, as indexed by significantly greater mean electromyogram responses during ice water testing. This bladder hypersensitivity did not require adult re-inflammation to manifest. Hypersensitivity was also observed with or without prior bladder distention, although the magnitude of electromyogram responses during ice water testing significantly correlated with the magnitude of electromyogram responses to bladder distention. Neonatally induced effects were not significantly related to estrous cycle phase. Exposure to menthol did not significantly enhance the overall magnitude of the electromyogram response to ice water testing in neonatally treated rats. Current results parallel those in a recent study showing that most patients with painful bladder syndrome/interstitial cystitis experience pain when undergoing ice water testing after previous urodynamic testing. These findings suggest that this animal model may be useful for understanding the etiology of and treatment for painful bladder syndrome/interstitial cystitis.

Sensory Denervation Reduces Visceral Hypersensitivity in Adult Rats Exposed to Chronic Unpredictable Stress: Evidences of Neurogenic Inflammation

The purpose of this study is to provide evidence of neurogenic inflammation in chronic unpredictable stressed rats with the changes of visceral sensitivity, number of mast cells, and close proximity among mast cell-nerve-blood vessels. We found that (1) capsaicin denervation blocked stress-induced increase of visceral sensitivity, while doxantrazole presented a partial blocking; (2) capsaicin denervation blocked stress-induced enhancement of the proximity of mast cell-nerve fiber-blood vessels and blood vessel damage, while doxantrazole showed no effects on these; (3) doxantrazole blocked stress-induced increases of the MPO activity, the number and the degranulation of mast cells in the colon; (4) sensory denervation and doxantrazole had no effects on stress-induced behavioral inhibition. These results suggest that capsaicin-sensitive sensory fibers play a key role in stress-induced visceral hypersensitivity and the ultrastructural changes, mast cells play an important role in the generation of stress-induced colon inflammation.

S1823 Do Mast Cells Contribute to Visceral Hypersensitivity in Adult Rats Following Neonatal Psychological Stress?

S1823 Do Mast Cells Contribute to Visceral Hypersensitivity in Adult Rats Following Neonatal Psychological Stress?

Long‐term colonic hypersensitivity in adult rats induced by neonatal unpredictable vs predictable shock

Our goal was to examine the relationship between early life trauma and the development of visceral hypersensitivity in later life in irritable bowel syndrome (IBS). Rat pups underwent neonatal conditioning: (i) paired odour-shock, where odour is a predictable shock signal, (ii) unpaired odour-shock, where odour is an unpredictable shock signal or (iii) control odour-only with odour presentations and handling without shock. At maturity, colorectal sensitivity was measured as a visceromotor behavioural response. In adulthood, colorectal distension (CRD) induced a pressure-dependent increase in the number of abdominal muscle contractions all three experimental groups. However, compared to animals that had received control odour-only presentations in infancy, there was an attenuated response to CRD in animals previously exposed to neonatal predictable shock pups and an exaggerated response in the animals previously exposed to neonatal unpredictable shock. Adult responses to CRD were altered by infant experience with shock trauma. However, depending on the context of that early life trauma, there are major differences between the long-term effects of that early life trauma on colonic sensitivity compared to controls. These results strengthen the link between early life trauma and adult IBS, and suggest that unpredictable trauma is a critical factor for later life disorders.

Mechanical Pain Hypersensitivity after Incisional Surgery Is Enhanced in Rats Subjected to Neonatal Peripheral Inflammation

Neonatal pain and inflammation may lead to a long-term effect on nociceptive processing in adults. The current study examined the characteristics of postoperative incisional pain behaviors in adult rats that were subjected to neonatal peripheral inflammation. Rat pups received a subcutaneous injection of saline or carrageenan into the plantar surface of the left hind paw at postnatal day 1. Naive pups were used as the control. Paw withdrawal thresholds to punctuate mechanical stimuli were examined at postnatal days 35, 42, and 49. After rats received a plantar incision on the left or right hind paw at postnatal day 50, paw withdrawal thresholds were measured at 4 h, 1 day, 2 days, 3 days, 5 days, and 7 days after incision. In addition, spinal cord Fos expression was detected at 2 h after incision. Finally, the effects of intrathecal N-methyl-D-aspartate receptor antagonists DL-2-amino-5-phosphonovaleric acid and dizocilpine and the nitric oxide synthase inhibitor L-N-nitro-arginine methylester on incisional pain were examined at 4 h after incision. Although the rats subjected to neonatal peripheral carrageenan injection developed mechanical hypoalgesia in bilateral hind paws at baseline, they displayed increased spinal cord Fos expression at 2 h and exaggerated mechanical pain hypersensitivity at 4 h (but not at other time points) after plantar incision. Intrathecal DL-2-amino-5-phosphonovaleric acid, dizocilpine, and L-N-nitro-arginine methylester significantly attenuated incision-induced mechanical pain hypersensitivity at 4 h after incision in the neonatally carrageenan-treated rats, but not in the naive or neonatally saline-treated rats. The authors' results suggest that early inflammatory insults during the neonatal period could produce excessive incision-associated mechanical pain hypersensitivity in adult rats. Spinal cord N-methyl-D-aspartate receptors and downstream nitric oxide signaling might contribute to this abnormal pain hypersensitivity, although the mechanisms underlying the long-term effect of neonatal inflammation are still unclear.