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Diagram showing the basic mechanism of visceral pain and hyperalgesia. 5‐HT, 5‐hydroxytryptamine; ASIC, acid‐sensing ion channel; ATP, adenosine triphosphate; BK, bradykinin; CGRP, calcitonin gene related peptide; DRASIC, dorsal root acid sensing ionic channel; DRG, dorsal root ganglion; NGF, nerve cycloxygenase; NMDA, N‐methyl‐D‐aspartate; P, pain neurons; PG, prostaglandin; SP, substance‐P; T, tactile; TRPV1, transient receptor potential vanilloid type 1
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Acute pain, provoked generally after the activation of peripheral nociceptors, is an adaptive sensory function that alerts the individual to avoid noxious stimuli. However, uncontrolled acute pain has a maladaptive role in sensory activity leading to development of a chronic pain state which persists even after the damage is resolved, or in some ca...
Citations
... Control of visceral pain is challenging in both human and veterinary medicine [1][2][3][4]. Differently from somatic pain, visceral pain is diffused, poorly localized, and it is associated with a vegetative autonomic response. Visceral nociception causes pain referred to other locations due to viscero-somatic and viscero-visceral synaptic convergences [4,5]. ...
... Differently from somatic pain, visceral pain is diffused, poorly localized, and it is associated with a vegetative autonomic response. Visceral nociception causes pain referred to other locations due to viscero-somatic and viscero-visceral synaptic convergences [4,5]. The autonomic nervous system contributes to the sensory innervation of viscera; sympathetic fibres run along sensitive afferences (mainly C fibres) and play a major role in the transmission of visceral pain [4,5]. ...
... Visceral nociception causes pain referred to other locations due to viscero-somatic and viscero-visceral synaptic convergences [4,5]. The autonomic nervous system contributes to the sensory innervation of viscera; sympathetic fibres run along sensitive afferences (mainly C fibres) and play a major role in the transmission of visceral pain [4,5]. ...
Celiac plexus block (CPB) and neurolysis (CPN) are used for pain management in people suffering from abdominal tumours or chronic pancreatitis. The fluoroscopically guided approach common in human medicine has not been described in veterinary settings. The aim of this study was to describe a fluoroscopic approach to the celiac plexus (CP) in fresh pig cadavers. Twelve animals were included in the procedure. Cadavers were positioned in sternal position and, under fluoroscopic guidance, a Chiba needle was inserted parasagittal at 6 cm from the spinal midline at the level of the last thoracic vertebra. From the left side, the needle was directed medio-ventrally with a 45° angle towards the T15 vertebral body; once the vertebral body was contacted, the needle was advanced 1 cm ventrally towards the midline. Iodinated contrast was injected to confirm the location. Following this, 2 mL of dye (China ink) was injected. A laparotomy was performed, and dyed tissue was dissected and prepared for both histochemical and immunohistochemical techniques. In 10 out of 12 samples submitted for histological evaluation, nervous tissue belonging to CP was observed. Fluoroscopy guidance allows for feasible access to the CP in swine cadavers in this study. Further studies are warranted to determine the efficacy of this technique in swine and other veterinary species.
... At present, there are many different types of models for studying visceral pain. These models are generated in many different ways and can meet the demands of modern scientific research (Regmi and Shah, 2020). However, there is still considerable scope for improvement; for example, the application and generation of these models need to be simpler, more stable and easier to control. ...
Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and can exert serious effects on a patient’s physical and mental health. According to modeling stimulation protocols, the current animal models of visceral pain mainly include the mechanical dilatation model, the ischemic model, and the inflammatory model. Acupuncture can exert analgesic effects by integrating and interacting input signals from acupuncture points and the sites of pain in the central nervous system. The brain nuclei involved in regulating visceral pain mainly include the nucleus of the solitary tract, parabrachial nucleus (PBN), locus coeruleus (LC), rostral ventromedial medulla (RVM), anterior cingulate cortex (ACC), paraventricular nucleus (PVN), and the amygdala. The neural circuits involved are PBN-amygdala, LC-RVM, amygdala-insula, ACC-amygdala, claustrum-ACC, bed nucleus of the stria terminalis-PVN and the PVN-ventral lateral septum circuit. Signals generated by acupuncture can modulate the central structures and interconnected neural circuits of multiple brain regions, including the medulla oblongata, cerebral cortex, thalamus, and hypothalamus. This analgesic process also involves the participation of various neurotransmitters and/or receptors, such as 5-hydroxytryptamine, glutamate, and enkephalin. In addition, acupuncture can regulate visceral pain by influencing functional connections between different brain regions and regulating glucose metabolism. However, there are still some limitations in the research efforts focusing on the specific brain mechanisms associated with the effects of acupuncture on the alleviation of visceral pain. Further animal experiments and clinical studies are now needed to improve our understanding of this area.
... Most animal models of visceral pain are based on the intraperitoneal administration of a chemical stimulus which induces sensitization of the peripheral and central pain pathways. Acetic acid, 2,4,6-trinitrobenzene sulfonic acid, zymosan and cyclophosphamide are the most frequently used, inducing symptoms in animals similar to those seen in patients suffering from this condition [22][23][24]. One major limitation of using these chemical stimuli is the lack of reproducibility in the biological response [25]. ...
... Further, we investigated if paclitaxel-induced visceral pain is followed by mechanical and thermal hypersensitivity. Based on the idea that inflammatory agents can activate nociceptors connected to unmyelinated C and thinly myelinated Aδ fibers, which are responsible for hypersensitivity, we chose to determine thermal and mechanical hypersensitivity after a single dose of paclitaxel [23]. Additionally, paclitaxel-associated acute pain syndrome is an important adverse reaction described by approximately 58% of patients [53]. ...
Visceral pain is a unique clinical entity that lacks an effective and safe treatment. Proper preclinical models are essential for assessing new drugs developed for the treatment of this pathology. Few studies report that paclitaxel, an antineoplastic agent, can be used to induce visceral pain in laboratory animals. Our purpose was to investigate the reproducibility of these studies and to develop an animal method that would allow assessing consistent visceral pain. In this study, we used four doses of paclitaxel (3 mg × kg−1; 5 mg × kg−1; 10 mg × kg−1 and 15 mg × kg−1). Visceral pain was evaluated using a scale of abdominal pain immediately after the administration of a single dose of paclitaxel to rats. Tactile and thermal hypersensitivity were assessed using von Frey filaments and the tail flick test initially, at 24 h and 48 h after administration. Rats experienced visceral pain and mechanical and thermal hypersensitivity 24 h after the administration of paclitaxel. The intensity of the pain was increased in a dose-dependent manner with the highest intensity of effect being observed after the administration of a dose of 15 mg × kg−1. Paclitaxel induces visceral pain. The dosage varies depending on the employed strain of rat. This method allows for assessing the efficacy of analgesics to be useful against visceral pain if the paclitaxel dose is adjusted accordingly to the animal strain.
... [5][6][7] Taking this into account, numerous animal models have been developed for the assessment of visceral sensitivity in normal conditions or in states of sensitization. A systematic review of these models is out of the scope of the present work and can be found [8][9][10][11] Several animal models of intestinal hypersensitivity have been developed based on the evidence that inflammation seems to be a pathophysiological component of inflammatory and functional GI disorders, as mentioned above. Overall, postinflammatory models have been based on the local administration (intracolonic enemas) of different active compounds (such as acetic acid, capsaicin, mustard oil, zymosan, trinitrobenzene sulfonic acid (TNBS)-or dinitrobenzene sulfonic acid (DNBS)) [12][13][14][15][16] or the experimental infection with biological agents (such as Trichinella spiralis, Nippostrongylus brasiliensis or Campylobacter species). ...
... 1,2 Taking this into account, animal models to study visceral pain arising from the gut are largely based on the induction of inflammation or irritation (with the consequent immune activation) of the GI tract. 8,9,11,52 In this context, DSS-induced colitis is a well-validated and accepted model of human F I G U R E 5 Effect of DSS-induced colitis on VMR responses to phasic repetitive CRD. A: VMRs to repetitive phasic CRD in healthy and DSS-induced colitic rats. ...
Background
Persistent visceral hypersensitivity is a key component of functional and inflammatory gastrointestinal diseases. Current animal models fail to fully reproduce the characteristics of visceral pain in humans, particularly as it relates to persistent hypersensitivity. This work explores the validity of DSS‐induced colitis in rats as a model to mimic chronic intestinal hypersensitivity.
Methods
Exposure to DSS (5% for 7 days) was used to induce colitis in rats. Thereafter, changes in viscerosensitivity (visceromotor responses to colorectal distension—CRD), the presence of somatic referred pain (mechanosensitivity of the hind paws, von Frey test) and the expression (qRT‐PCR) of sensory‐related markers (colon, lumbosacral DRGs, and lumbosacral spinal cord) were assessed at different times during the 35 days period after colitis induction.
Results
Following colitis, a sustained increase in visceromotor responses to CRD were observed, indicative of the presence of visceral hypersensitivity. Responses in animals without colitis remained stable over time. In colitic animals, somatic referred hypersensitivity was also detected. DSS‐induced colitis was associated to a differential expression of sensory‐related markers (with both pro‐ and anti‐nociceptive action) in the colon, lumbosacral DRGs and lumbosacral spinal cord; indicating the presence of peripheral and central sensitization.
Conclusions and Inferences
DSS‐induced colitis in rats is associated to the generation of a long‐lasting state of visceral (colonic) hypersensitivity, despite clinical colitis resolution. This model reproduces the changes in intestinal sensitivity characteristics of inflammatory and functional gastrointestinal disorders in humans and can be used in the characterization of new pharmacological treatments against visceral pain.
... Giving that changes in inflammatory factors, including TNFα, IL-1β, IL-6, IL-10, and iNOS, are a major characteristic of the sepsis model, 45,46 we measured the inflammatory cytokines after LPS treatment. We observed changes in inflammatory cytokines at different timepoints after LPS treatment (S3). ...
Background:
Inflammation is a complex physiological and pathological process. Although many types of inflammation are well characterized, their physiological functions are largely unknown. tRNA aspartic acid methyltransferase 1 (TRDMT1) has been implicated as a stress-related protein, but its intrinsic biological role is unclear.
Methods:
We constructed a Trdmt1 knockout rat and adopted the LPS-induced sepsis model. Survival curve, histopathological examination, expression of inflammatory factors, and protein level of TLR4 pathway were analyzed.
Results:
Trdmt1 deletion had no obvious impact on development and growth. Trdmt1 deletion slightly increased the mortality during aging. Our data showed that Trdmt1 strongly responded in LPS-treated rats, and Trdmt1 knockout rats were vulnerable to LPS treatment with declined survival rate. We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS-treated knockout rats compared with control rats. Further studies showed upregulated TNF-α level in liver, spleen, lung, and serum tissues, which may be explained by enhanced p65 and p38 phosphorylation.
Conclusions:
Our data demonstrated that Trdmt1 plays a protective role in inflammation by regulating the TLR4-NF-κB/MAPK-TNF-α pathway. This work provides useful information to understand the TRDMT1 function in inflammation.
... Another limitation of this study would be its translationality to humans [56,57]. Even though no animal model can mimic human visceral pain perfectly, visceral pain models have allowed the study of the pathophysiology of the disease, as well as the efficacy of potential analgesics [58,59]. Moreover, while interspecies differences have been described in BoNT sensitivity [60], protein engineering can produce BoNTs with improved affinity for human receptors to bypass these discrepancies [61]. ...
For the past two decades, botulinum neurotoxin A (BoNT/A) has been described as a strong candidate in the treatment of pain. With the production of modified toxins and the potential new applications at the visceral level, there is a real need for tools allowing the assessment of these compounds. In this study, we evaluated the jejunal mesenteric afferent nerve assay to investigate BoNT/A effects on visceral nociception. This ex vivo model allowed the continuous recording of neuronal activity in response to various stimuli. BoNT/A was applied intraluminally during three successive distensions, and the jejunum was distended every 15 min for 3 h. Finally, samples were exposed to external capsaicin. BoNT/A intoxication was validated at the molecular level with the presence of cleaved synaptosomal-associated protein of 25 (SNAP25) in nerve terminals in the mucosa and musculosa layers 3 h after treatment. BoNT/A had a progressive inhibitory effect on multiunit discharge frequency induced by jejunal distension, with a significant decrease from 1 h after application without change in jejunal compliance. The capsaicin-induced discharge was also affected by the toxin. This assay allowed the description of an inhibitory effect of BoNT/A on afferent nerve activity in response to distension and capsaicin, suggesting BoNT/A could alleviate visceral nociception.
... Among the main animal models that have been developed, there are specific systems of distension of hollow organs or of the capsule of parenchymatous organs (insertion of small balloons that can be inflated), evoking quantifiable responses such as contraction of the abdominal and pelvic muscles (evaluated by electromyography) or an increase in blood pressure and heart rate (evaluated by surgical implantation of intravenous catheters). Inflammatory pain is also evoked by injecting irritants (2,4,6-trinitrobenzenesulfonic acid (TNBS) diluted in alcohol, acetic acid, zymosan, acrolin, or cyclophosphamide) directly into the esophagus, ileus, colon, or urinary bladder, and the pain response is evaluated with electromyography or analgesiometry [50]. ...
In sea turtle rescue and rehabilitative medicine, many of the casualties suffer from occurrences that would be considered painful in other species; therefore, the use of analgesic drugs should be ethically mandatory to manage the pain and avoid its deleterious systemic effects to guarantee a rapid recovery and release. Nonetheless, pain assessment and management are particularly challenging in reptilians and chelonians. The available scientific literature demonstrates that, anatomically, biochemically, and physiologically, the central nervous system of reptiles and chelonians is to be considered functionally comparable to that of mammals albeit less sophisticated; therefore, reptiles can experience not only nociception but also “pain” in its definition of an unpleasant sensory and emotional experience. Hence, despite the necessity of appropriate pain management plans, the available literature on pain assessment and clinical efficacy of analgesic drugs currently in use (prevalently opioids and NSAIDs) is fragmented and suffers from some basic gaps or methodological bias that prevent a correct interpretation of the results. At present, the general understanding of the physiology of reptiles’ pain and the possibility of its reasonable treatment is still in its infancy, considering the enormous amount of information still needed, and the use of analgesic drugs is still anecdotal or dangerously inferred from other species.
... Such inflammation will lead to a sensitization of the system such that even minor mechanical stimulation will lead to enhanced responses. 138,180 Peritoneal Irritants ...
Acetaminophen (APAP) in humans has robust effects with a high therapeutic index in altering postoperative and inflammatory pain states in clinical and experimental pain paradigms with no known abuse potential. This review considers the literature reflecting the preclinical actions of acetaminophen in a variety of pain models. Significant observations arising from this review are as follows: 1) acetaminophen has little effect upon acute nociceptive thresholds; 2) acetaminophen robustly reduces facilitated states as generated by mechanical and thermal hyperalgesic end points in mouse and rat models of carrageenan and complete Freund’s adjuvant evoked inflammation; 3) an antihyperalgesic effect is observed in models of facilitated processing with minimal inflammation (eg, phase II intraplantar formalin); and 4) potent anti-hyperpathic effects on the thermal hyperalgesia, mechanical and cold allodynia, allodynic thresholds in rat and mouse models of polyneuropathy and mononeuropathies and bone cancer pain. These results reflect a surprisingly robust drug effect upon a variety of facilitated states that clearly translate into a wide range of efficacy in preclinical models and to important end points in human therapy. The specific systems upon which acetaminophen may act based on targeted delivery suggest both a spinal and a supraspinal action. Review of current targets for this molecule excludes a role of cyclooxygenase inhibitor but includes effects that may be mediated through metabolites acting on the TRPV1 channel, or by effect upon cannabinoid and serotonin signaling. These findings suggest that the mode of action of acetaminophen, a drug with a long therapeutic history of utilization, has surprisingly robust effects on a variety of pain states in clinical patients and in preclinical models with a good therapeutic index, but in spite of its extensive use, its mechanisms of action are yet poorly understood.
... Examination of pain processing in the brain in response to CRD • Non-invasive (Lazovic et al., 2005;Johnson et al., 2010;Wouters et al., 2012) • Allows examination of the brain in live animals • Labour intensive • Time consuming • Lacks objectivity and reproducibility (Regmi and Shah 2020) *This is also well reviewed in Regmi and Shah 2020 (doi: https://doi.org//10.1002/ame2.12130). ...
Visceral pain refers to pain arising from the internal organs and is distinctly different from the expression and mechanisms of somatic pain. Diseases and disorders with increased visceral pain are associated with significantly reduced quality of life and incur large financial costs due to medical visits and lost work productivity. In spite of the notable burden of illness associated with those disorders involving increased visceral pain, and some knowledge regarding etiology, few successful therapeutics have emerged, and thus increased attention to animal models of visceral hypersensitivity is warranted in order to elucidate new treatment opportunities.
Altered microbiota-gut-brain (MGB) axis communication is central to the comorbid gastrointestinal/psychiatric diseases of which increased visceral (intestinal) sensitivity is a hallmark. This has led to a particular focus on intestinal microbiome disruption and its potential role in the etiology of heightened visceral pain. Here we provide a review of studies examining models of heightened visceral pain due to altered bidirectional communication of the MGB axis, many of which are conducted on a background of stress exposure. We discuss work in which the intestinal microbiota has either been directly manipulated (as with germ-free, antibiotic, and fecal microbial transplantation studies) or indirectly affected through early life or adult stress, inflammation, and infection. Animal models of visceral pain alterations with accompanying changes to the intestinal microbiome have the highest face and construct validity to the human condition and are the focus of the current review.
... The pain can be managed effectively when its signs can be assessed reliably and accurately [7]. The different methods of pain a measurement in animal models has been described very recently [11]. There is no any ideal method that validates and measures the pain objectively. ...
The present study was aimed to evaluate the comparative efficacies of incisional local anesthetics following rumenotomy in
Black Bengal goats. Goats (N=40) were randomly allocated equally into LID, LID+A, BUP and SAL groups. After overnight fasting, goats were injected with 0.5 mg kg-1 meloxicam subcutaneously and 1 mg kg-1 diazepam intramuscularly. Left paravertebral analgesia were achieved in goats of aforementioned groups using 5 ml of 2% lidocaine, 2% lidocaine plus adrenaline, 0.5% bupivacaine and 0.9% NaCl. The rumenotomy was performed and before closing the skin, 2% lidocaine (7 mg kg-1), 2% lidocaine plus adrenaline (7 mg kg-1) and 0.5% bupivacaine (2.5 mg kg-1) were infiltrated incisionally in goats of LID, LID+A, BUP groups, respectively. However, the goats of SAL group were infiltrated incisionally with 5 ml of 0.9% saline. Pain and wound tenderness were evaluated by pricking and manual pressing around the wound whereas sedation was assessed by observing behavioral manifestations using dynamic interactive visual analogue scale before premedication, 0.5, 1, 2, 4, 8 and 22 hours after surgery. Data were analyzed using one-way ANOVA followed by Bonferroni test.
Goats of LID and LID+A groups showed moderately less pain up to 4 hours. BUP groups exhibited the least pain at 4 and
8 hours. LID group measured lower (P<0.01) WT scores than SAL or BUP group at 0.5 hour. All local anesthetics treated goats exhibited less WT scores at 1-22 hours. Goats of all groups were sedated highest at 0.5 hour and sedation scores were decreased thereafter. The preemptively administered meloxicam combined with incisional infiltration of lidocaine provided excellent analgesia for a short period whereas lidocaine plus adrenaline and bupivacaine provided analgesia for a longer period. A multimodal analgesic approach including incisional local analgesic is suggested for postoperative pain control.
Keywords: Goats; Local Analgesics; Pain Rumenotomy; Sedation; Wound Tenderness
