Since the initial description by Wall Wall, P.D., 1967. The laminar organization of dorsal horn and effects of descending impulses. J. Neurophysiol. 188, 403-423 of tonic descending inhibitory ...control of dorsal horn neurons, several studies have aimed to characterize the role of various brain centers in the control of nociceptive input to the spinal cord. The role of brainstem centers in pain inhibition has been well documented over the past four decades. Lesion to peripheral nerves results in hypersensitivity to mild tactile or cold stimuli (allodynia) and exaggerated response to nociceptive stimuli (hyperalgesia), both considered as cardinal signs of neuropathic pain. The increased interest in animal models for peripheral neuropathy has raised several questions concerning the rostral conduction of the neuropathic manifestations and the role of supraspinal centers, especially brainstem, in the inhibitory control or in the abnormal contribution to the maintenance and facilitation of neuropathic-like behavior. This review aims to summarize the data on the ascending and descending modulation of neuropathic manifestations and discusses the recent experimental data on the role of supraspinal centers in the control of neuropathic pain. In particular, the review emphasizes the importance of the reciprocal interconnections between the analgesic areas of the brainstem and the pain-related areas of the forebrain. The latter includes the cerebral limbic areas, the prefrontal cortex, the intralaminar thalamus and the hypothalamus and play a critical role in the control of pain considered as part of an integrated behavior related to emotions and various homeostatic regulations. We finally speculate that neuropathic pain, like extrapyramidal motor syndromes, reflects a disorder in the processing of somatosensory information.
•Single session of AMN stimulation induced unilateral increase in neurogenesis.•Multiple sessions of AMN stimulation induced bilateral increase in neurogenesis.•Single session of stimulation ...increased rat exploratory behavior at 4 weeks.•Multiple stimulation sessions increased rat exploratory behavior at 1 and 4 weeks.
Deep brain stimulation (DBS) has shown positive clinical results in neurodegenerative diseases. Previous work from our group showed that a single session of DBS to the anteromedial thalamic nucleus (AMN) in awake rats, increased proliferation of stem/progenitor cells in the dentate gyrus (DG) of the hippocampus. We thought to examine the effect of single versus multiple sessions of DBS to the AMN in modulating adult hippocampal neurogenesis. Rats received unilateral single session, multiple sessions or no electrical stimulation (sham) in the right AMN. Rats received 5’-bromo-2’-deoxyuridine (BrdU) injections and were followed over a period of 1 week or 4 weeks. Single session of electrical stimulation induced a 1.9-fold increase in the number of proliferating BrdU positive cells after one week from stimulation and a 1.8-fold increase at four weeks post stimulation, both in the ipsilateral DG. As for multiple sessions of stimulation, they induced a 3- fold increase that extended to the contralateral DG after 4 weeks from stimulation. Spatial reference memory was tested in the Y-maze test by examining novel arm exploration. Both single and multiple sessions of stimulation prompted an increase in novel arm exploration at week 4, while only the multiple sessions of stimulation had this effect starting from week 1. This study demonstrates that sustained activation of the AMN boosts neurogenesis and improves spatial reference memory.
The nervous system and the gastrointestinal (GI) tract share several common features including reciprocal interconnections and several neurotransmitters and peptides known as gut peptides, ...neuropeptides or hormones. The processes of digestion, secretion of digestive enzymes and then absorption are regulated by the neuro-endocrine system. Luminal glucose enhances its own absorption through a neuronal reflex that involves capsaicin sensitive primary afferent (CSPA) fibres. Absorbed glucose stimulates insulin release that activates hepatoenteric neural pathways leading to an increase in the expression of glucose transporters. Adrenergic innervation increases glucose absorption through α1 and β receptors and decreases absorption through activation of α2 receptors. The vagus nerve plays an important role in the regulation of diurnal variation in transporter expression and in anticipation to food intake. Vagal CSPAs exert tonic inhibitory effects on amino acid absorption. It also plays an important role in the mediation of the inhibitory effect of intestinal amino acids on their own absorption at the level of proximal or distal segment. However, chronic extrinsic denervation leads to a decrease in intestinal amino acid absorption. Conversely, adrenergic agonists as well as activation of CSPA fibres enhance peptides uptake through the peptide transporter PEPT1. Finally, intestinal innervation plays a minimal role in the absorption of fat digestion products. Intestinal absorption of nutrients is a basic vital mechanism that depends essentially on the function of intestinal mucosa. However, intrinsic and extrinsic neural mechanisms that rely on several redundant loops are involved in immediate and long-term control of the outcome of intestinal function.
Abstract Contradictory results have been reported regarding the role of inflammatory mediators in the central nervous system in mediating neuropathic pain and inflammatory hyperalgesia following ...peripheral nerve injury or localized inflammation. The present study aims to correlate between the mRNA expression and protein secretion of proinflammatory cytokines and nerve growth factor (NGF), in the dorsal root ganglia (DRGs), spinal cord, brainstem and thalamus, and pain-related behavior in animal models of peripheral mononeuropathy and localized inflammation. Different groups of rats ( n = 8, each) were subjected to either lesion of the nerves of their hindpaws to induce mononeuropathy or intraplantar injection of endotoxin (ET) and were sacrificed at various time intervals. TNF-α, IL-1β and NGF mRNA expression and protein levels in the various centers involved in processing nociceptive information were determined, by RT-PCR and ELISA. Control groups were either subjected to sham surgery or to saline injection. Mononeuropathy and ET injection produced significant and sustained increases in the mRNA expression and protein levels of TNF-α, IL-1β and NGF in the ipsilateral and contralateral DRGs, spinal cord, and brainstem. No significant and consistent changes in the mRNA expression of cytokines were noticed in the thalamus, while a down regulation of the NGF-mRNA level was observed. The temporal and spatial patterns of the observed changes in mRNA expression of cytokines and NGF are not closely in phase with the observed allodynia and hyperalgesia in the different models, suggesting that the role of these mediators may not be reduced exclusively to the production and maintenance of pain.
•Two different chemical sympathectomy techniques on the eruption of rat incisors.•Eruption process affected according to the applied sympathectomy.•New insight to an old subject with explanations to ...some unanswered questions.
Intact neural supply is necessary for tooth eruption. Sympathetic denervation accelerates or decelerates the eruption rate depending on the tooth condition (intact or injured). The aim of this study is to reexamine the role of the sympathetic innervation, through the observation of the effects of pre or post ganglionic chemical sympathectomy on the eruption of intact rat incisors.
Different groups of rats were subjected to either ganglionic or peripheral chemical sympathectomy and the observed effects on incisor eruption were compared to those made on intact/sham groups or on rats subjected to inferior alveolar nerve (IAN) lesion.
The total amount of eruption in control/naïve rats, measured over a total period of 144 h, was 3 ± 0.15 mm and decreased to 2.57 ± 0.06 mm (n = 8; p < 0.01) or 2.8 ± 0.10 mm (n = 8; p < 0.05) following treatment with guanethidine and hexamethonium, respectively. This amount decreased to 1.8 ± 0.14 mm (p < 0.001 vs. control, n = 7; or p < 0.01 vs. sham, n = 5) in rats subjected to IAN lesion.
Sympathectomy delayed tooth eruption. Blocking the sympathetic effectors with guanethidine exerted more potent effects than ganglionic block with hexamethonium. Intact sympathetic supply is required for tooth growth under normal conditions.
•Colitis manifests with diarrhea, hypoproteinemia and malabsorption of nutrients.•A novel model of localized colonic injury induced by bipolar electro-cautery has been described.•In this model, ...up-regulation of proinflammatory cytokines protein and mRNA occurs in the whole gut.•A decreased jejunal amino acid absorption swiftly follows localized colonic injury.•The spreading effects of colitis to non-inflamed intestines may involve neuro-humoral pathways.
Colitis is associated with functional abnormalities in proximal non-inflamed gut areas, but animal models to study small bowel dysfunction in colitis have limitations. This study aims to determine small intestinal alanine absorption and cytokine expression in a novel model of colonic ulceration induced by electro-cautery.
A descending colon ulcer was induced in rats by a bipolar electro-cautery probe. Ulcer score was determined using Satoh’s criteria. Jejunal alanine absorption was measured immediately and at different time intervals post ulcer induction. Levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) protein and m-RNA were determined in mucosal scrapings obtained from the colon, duodenum, jejunum and ileum at various time intervals after colonic ulcer induction.
The mean ulcer score was 3 up to 48h, followed by healing by 96h post ulcer induction. Small bowel histology was normal throughout. Jejunal alanine absorption was reduced by 12–34% immediately and up to 72h after cautery and returned to normal at 96h. IL-1 and TNF-α mRNA increased significantly in the colon, duodenum, jejunum and ileum 3h post electro-cautery and returned to normal at 48h, while that of IL-6 increased significantly at 48h post ulcer induction. Similarly, IL-1, IL-6 and TNF-α protein levels increased in the duodenum, jejunum, ileum and colon up to 48h post ulcer induction.
Electrically induced localized colonic injury increased production of pro-inflammatory cytokines in non-inflamed segments of the small intestine and was associated with derangements of jejunal absorptive function.
Previous studies have suggested a link between urinary tract infections (UTIs) and cognitive impairment. One possible contributing factor for UTI-induced cognitive changes that has not yet been ...investigated is a potential alteration in hippocampal neurogenesis. In this study, we aim to investigate the effect of UTI on brain plasticity by specifically examining alterations in neurogenesis. Adult male Sprague Dawley rats received an intra-urethral injection of an Escherichia coli (E. coli) clinical isolate (108 CFU/mL). We found that rats with a UTI (CFU/mL ≥ 105) had reduced proliferation of neural stem cells (NSCs) at an early time point post infection (day 4) and neurogenesis at a later time point (day 34). This was associated with the decreased expression in mRNA of BDNF, NGF, and FGF2, and elevated expression of IL-1β in the hippocampus at 6 h post infection, but with no changes in optical intensity of the microglia and astrocytes. In addition, infected rats spent less time exploring a novel arm in the Y-maze test. Treatment with an anti-inflammatory drug did not revert the effect on NSCs, while treatment with antibiotics further decreased the basal level of their proliferation. This study presents novel findings on the impact of urinary tract infections on hippocampal neurogenesis that could be correlated with cognitive impairment.
Increased levels of pro- and anti-inflammatory cytokines were observed in various segments of histologically-intact small intestine in animal models of acute and chronic colitis. Whether these ...cytokines are produced locally or spread from the inflamed colon is not known. In addition, the role of gut innervation in this upregulation is not fully understood. To examine whether cytokines are produced de novo in the small intestine in two rat models of colitis; and to investigate the role of capsaicin-sensitive primary afferents in the synthesis of these inflammatory cytokines. Colitis was induced by rectal instillation of iodoacetamide (IA) or trinitrobenzene sulphonic acid (TNBS) in adult Sprague-Dawley rats. Using reverse transcriptase (RT) and real-time PCR, TNF-α, and IL-10 mRNA expression was measured in mucosal scrapings of the duodenum, jejunum, ileum and colon at different time intervals after induction of colitis. Capsaicin-sensitive primary afferents (CSPA) were ablated using subcutaneous injections of capsaicin at time 0, 8 and 32 h, and the experiment was repeated at specific time intervals to detect any effect on cytokines expression. TNF-α mRNA expression increased by 3-40 times in the different intestinal segments (p<0.05 to p<0.001), 48h after IA-induced colitis. CSPA ablation completely inhibited this upregulation in the small intestine, but not in the colon. Similar results were obtained in TNBS-induced colitis at 24 h. Intestinal IL-10 mRNA expression significantly decreased at 12 h and then increased by 6-43 times (p<0.05 to p<0.001) 48h after IA administration. This increase was abolished in rats subjected to CSPA ablation except in the colon, where IL-10 further increased by twice (p<0.05). In the TNBS group, there was 4-12- and 4-7-fold increases in small intestinal IL-10 mRNA expression at 1 and 21 days after colitis induction, respectively (both p<0.01). This increase was not observed in rats pretreated with capsaicin. Capsaicin-treated and untreated rats had comparable visual ulcer scores after colitis induction. Inflammatory cytokines are produced de novo in distant intestinal segments in colitis. CSPA fibers play a key role in the upregulation of this synthesis.
Cytokines, peptide hormones and neurotransmitters, as well as their receptors/ligands, are endogenous to the brain, endocrine and immune systems. These shared ligands and receptors are used as a ...common chemical language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune system. Interplay between the immune, nervous and endocrine systems is most commonly associated with the pronounced effects of stress on immunity. The hypothalamic–pituitary–adrenal (HPA) axis is the key player in stress responses; it is well established that both external and internal stressors activate the HPA axis. Cytokines are chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection. This review discusses current knowledge of cytokine signaling pathways in neuro–immune–endocrine interactions as viewed through the triplet HPA axis. In addition, we elaborate on HPA/cytokine interactions in oxidative stress within the context of nuclear factor-κB transcriptional regulation and the role of oxidative markers and related gaseous transmitters.
Based on significant amount of evidence, it is now generally believed, that one underlying cause for neurodegenerative diseases, could be dysregulation in inflammatory processes. The actual ...mechanisms involved are not yet well understood. Several studies have demonstrated the potent analgesic and anti-inflammatory actions of thymulin related peptide (PAT), in different animal pain models. In this study, we investigated the efficacy of PAT in a recently developed model of neuroinflammation, in conscious rats, caused by intracerbroventricular (ICV) injection of endotoxin (ET). Our results indicate that ICV injection of PAT alone did not elicit significant alteration of nociceptive thresholds, while ET injections produced significant thermal hyperalgesia and cold allodynia. Pretreatment with PAT resulted in significant alleviation of ET-induced hyperalgesia and increased body temperature. In other sets of experiments, ICV injection of ET resulted in a significant elevation in the concentration of pro-inflammatory mediators measured in different areas of the brain; this elevation was significantly following pretreatment with PAT. Taken together these results provide evidence in support of our hypothesis that as a potent anti-inflammatory and analgesic peptide, PAT might have potential therapeutic use for the treatment of neurodegenerative conditions induced by silent or overt inflammation.
►Neurodegenerative diseases, could be due to discrete inflammatory processes, but the actual mechanisms involved are not yet well understood. ►Thymulin related peptide (PAT) has established analgesic and anti-inflammatory properties. We aimed to test the effects of PAT Using an animal model for neuroinflammation. ►Pretreatment with PAT resulted in significant alleviation of Endotoxin-induced hyperalgesia and increased body temperature. ►Intracerebroventricular injection of endotoxin resulted in a significant elevation in the concentration of pro-inflammatory mediators in different areas of the brain, which was significantly attenuated following pretreatment with PAT. ►PAT might have potential therapeutic use for the treatment of neurodegenerative conditions induced by silent or overt inflammation.
