Animal Models Of Pain Research Articles

MiR-200a-3p Attenuates Neuropathic Pain by Suppressing the Bromodomain-Containing Protein 3-Nuclear Factor-κB Pathway.

MicroRNAs (miRNAs) have key roles in the pathological processes of neuropathic pain. Here, our aim was to elucidate the function of miR-200a-3p as well as its related regulatory mechanism in neuropathic pain. An animal model of neuropathic pain was established by chronic constriction injury (CCI) induction. The knockdown experiments are performed by injecting a lentiviral construct intrathecally. MiR-200a-3p and bromodomain-containing protein 3 (BRD3) expression in rat spinal cord was determined using RT-qPCR. The mechanical, thermal, and cold responses in animals were assessed at the indicated time after surgery. The levels of inflammatory cytokines in rat spinal cord were measured by ELISA. The changes in NF-κB signaling-related molecules in rat spinal cord were determined using western blot and immunofluorescence. MiR-200a-3p was underexpressed in CCI rats in a time-dependent manner. Overexpression of miR-200a-3p decreased mechanical hyperalgesia and thermal sensitivity to attenuate neuropathic pain in rats. BRD3 was targeted by miR-200a-3p. Additionally, downregulation of BRD3 inhibited neuropathic pain progression. Moreover, overexpression of BRD3 rescued the effect of miR-200a-3p on NF-κB signaling and neuropathic pain in CCI rats. MiR-200a-3p attenuates neuropathic pain via downregulating BRD3 to block NF-κB signaling.

Pregabalin produces analgesia in males but not females in an animal model of chronic widespread muscle pain.

Pregabalin, which acts on the α2δ-1 subunit of voltage-gated calcium channels, relieves ≥50% of pain in a third of individuals with fibromyalgia. Thus far, preclinical studies of pregabalin have predominantly used male animals. The purpose of our study was to investigate potential sex differences in the analgesic efficacy of pregabalin that may contribute to disparities in human outcomes. We used a mouse model of chronic widespread muscle pain (CWP) to test the effects of pregabalin on muscle hyperalgesia, nonreflexive pain, and motor behaviors. The CWP pain model combines 2 pH 4.0 saline injections, spaced 5 days apart, into the gastrocnemius muscle and produces bilateral muscle hyperalgesia. Furthermore, we explored sex differences in the mRNA and protein expression of the α2δ-1 subunit of voltage-gated calcium channels in the dorsal horn of the spinal cord and dorsal root ganglia after development of CWP. Pregabalin fully attenuated muscle hyperalgesia bilaterally in male but not female mice with equal motor deficits produced in both sexes. In addition, using the conditioned place preference test, mice of both sexes with CWP spent significantly more time in the pregabalin-paired chamber compared with baseline, but not significantly greater than pain-free controls. Chronic widespread muscle pain produced no changes in α2δ-1 subunit mRNA or protein expression in the dorsal horn of the spinal cord or dorsal root ganglia in either sex. Overall, these findings indicate pregabalin may be more effective in treating CWP in males, but the factors leading to these differences are not fully understood.

Psilocybin as a novel treatment for chronic pain.

Psychedelic drugs are under active consideration for clinical use and have generated significant interest for their potential as anti-nociceptive treatments for chronic pain, and for addressing conditions like depression, frequently co-morbid with pain. This review primarily explores the utility of preclinical animal models in investigating the potential of psilocybin as an anti-nociceptive agent. Initial studies involving psilocybin in animal models of neuropathic and inflammatory pain are summarised, alongside areas where further research is needed. The potential mechanisms of action, including targeting serotonergic pathways through the activation of 5-HT2A receptors at both spinal and central levels, as well as neuroplastic actions that improve functional connectivity in brain regions involved in chronic pain, are considered. Current clinical aspects and the translational potential of psilocybin from animal models to chronic pain patients are reviewed. Also discussed is psilocybin's profile as an ideal anti-nociceptive agent, with a wide range of effects against chronic pain and its associated inflammatory or emotional components.

Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons

Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we find that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs. Disruption of OMDs potentiated action potential firing in nociceptor DRG neurons and facilitated the opening of native hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels. This increased neuronal firing is partially due to an increased open probability and altered gating kinetics of HCN channels. The gating effect on HCN channels is likely due to a direct modulation of their voltage sensors by OMDs. In animal models of neuropathic pain, we observe reduced OMD size and a loss of HCN channel localization within OMDs. Additionally, cholesterol supplementation inhibited HCN channels and reduced neuronal hyperexcitability in pain models. These findings suggest that disturbances in lipid nanodomains play a critical role in regulating HCN channels within nociceptor DRG neurons, influencing pain modulation.

An Update on Emerging Regenerative Medicine Applications: The Use of Extracellular Vesicles and Exosomes for the Management of Chronic Pain.

Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain. In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood.

Effective Dose of Cocoa as a Preemptive Analgesic and Anti- Inflammatory Agent Assessed through Pain Scale and Tumor Necrosis Factor Alpha (TNF-α) in an Acute Pain Animal Model

Effective Dose of Cocoa as a Preemptive Analgesic and Anti- Inflammatory Agent Assessed through Pain Scale and Tumor Necrosis Factor Alpha (TNF-α) in an Acute Pain Animal Model

Neuroinflammatory Pathways Associated with Chronic Post-Thoracotomy Pain: A Review of Current Literature.

Chronic post-thoracotomy pain (CPTP) is a major clinical problem that affects up to 35-55% of patients undergoing thoracic incisions. Evidence suggests that multiple cellular signaling pathways and neuro-inflammatory mediators may play an essential role in the pathogenesis of CPTP. In this comprehensive review, we present the current evidence on the cellular signaling pathways and inflammatory changes associated with the initiation and maintenance of CPTP, focusing on the potential application of these findings in the clinical setting. An electronic search of Medline, EMBASE, Cochrane, Google Scholar, and ClinicalTrials.gov was performed, and 3652 abstracts were identified. After an initial abstract screening, 131 studies underwent a full-text review, and nine papers were eventually included in this review. Studies were included if they assessed the cellular signaling pathways or inflammatory processes associated with the induction and/or maintenance of CPTP. All the identified studies were pre-clinical studies conducted on animal models. Our search identified seven cellular pathways (NK-1 receptor (NK-1), Glutaminase 1, Toll-like receptor 4 (TLR4), Resolvins, Ror-2, Sonic hedgehog signaling (Shh), and Wnt5a/Wnts) and six cytokines (IL-1β, IL-6, IL-8, IL-10, IFN-γ, and TNF-α) that were investigated in the context of CPTP. Multiple cellular signaling pathways and inflammatory cytokines may play an important role in the neuroinflammatory changes associated with the induction and maintenance of chronic post-thoracotomy pain in animal models. However, the clinical impact and therapeutic utility of these neuroinflammatory changes in routine clinical practice have yet to be demonstrated.

Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings.

Despite major advancements in our understanding of its fundamental causes, pain-both acute and chronic-remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.

Intranasal administration of recombinant human BDNF as a potential therapy for some primary headaches

BackgroundIn addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors.MethodsIn a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration.ResultsBoth doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP.ConclusionsThe findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine.

RETRACTION: Development of an Experimental Animal Model for Lower Back Pain by Percutaneous Injury-Induced Lumbar Facet Joint Osteoarthritis.

J.-S. Kim, K. Ahmadinia, X. Li, J. L. Hamilton, S. Andrews, C. A. Haralampus, G. Xiao, H.-M. Sohn, J.-W. You, Y.-S. Seo, G. S. Stein, A. J. Van Wijnen, S.-G. Kim, and H.-J. Im, "Development of an Experimental Animal Model for Lower Back Pain by Percutaneous Injury-Induced Lumbar Facet Joint Osteoarthritis," Journal of Cellular Physiology 230, no. 11 (2015): 2837-2847, https://doi.org/10.1002/jcp.25015. The above article, published online on 9 April 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has occurred due to concerns related to the data presented in the article raised by the Office of Research Compliance at Rush University Medical Center following an investigation jointly conducted by Rush University and the Jesse Brown Veterans Affairs Medical Center (JBVAMC). Specifically, the journal has been made aware of discrepancies in the reported sample sizes for each of the three experimental groups in Figure 4A, with the indicated numbers exceeding the actual sample sizes. Additionally, image elements of the experimental data in Figure 7A and B were found to have been used by the same author(s) for publication elsewhere in a different scientific context. The corresponding author, Dr. Hee-Jeong Im Sampen, has been informed of the decision to retract but did not agree with it, as she is confident that any errors in the publication do not impact the reliability of the paper's findings. She also advised the editors that she stands ready to cooperate fully to make any necessary corrections. However, the article is retracted as the editors lost trust in the accuracy of the data and consider the conclusions invalid.

8808 Characterization and pre-clinical study on a novel hormonal compound with potent analgesic and anti-inflammatory properties

Abstract Disclosure: T. Antakly: Other; Self; Theriac Biomedical. A. Brox: Owner/Co-Owner; Self; Theriac Biomedical. J. Menezes: Advisory Board Member; Self; Theriac Biomedical. H.H. Zingg: None. Hormones and naturally occurring compounds with therapeutic benefits have provided the basis of some of the most celebrated drugs e.g. Taxol (extracted from the Pacific Hew tree) and Premarin, a hormone replacement therapy (extracted from horse urine). Our team has discovered and chemically identified a bioactive compound (called “HIP-2”) found in folk medicinal admixtures. It has unique analgesic and anti-inflammatory properties. The chemical structure of HIP-2 consists of small fatty acid molecules which bind and activate the PPAR-gamma transcription factor, and furthermore they have HDAC inhibitory properties. A synthetic replica of the bioactive compounds was obtained and administered orally or by injection in a single dosage form. Using animal models for pain and inflammation, HIP-2 has demonstrated an outstanding efficacy and safety profile in animals (rats, mice) rendered experimentally inflamed (e.g. carrageenan injection) or osteoarthritic (surgery or iodoacetate injection). Pain and inflammation have decreased (by up to 50%) after HIP-2 administration. Inflammatory cytokines biomarkers were also reduced by about 50% as compared to baseline or to the positive controls (classical NSAID’s). HIP-2, with an outstanding safety and efficacy profile, offers an advantage over currently available analgesic and anti-inflammatory drugs, which have significant draw-backs due to limited efficacy and significant side effects such as gastrointestinal bleeding/ulcers/perforation and cardiac toxicity (Advil, Celebrex), osteoporosis and immunosuppression (corticosteroids), or addiction (opioids). As a potential solution to these problems, HIP-2 is likely to be superior both at the safety and efficacy levels. The HIP-2 IMP was cleared by FDA and is entering Phase 2 clinical trials. Presentation: 6/3/2024

Closed-loop neural interfaces for pain: Where do we stand?

Advances in closed-loop neural interfaces and neuromodulation have offered a potentially effective and non-addictive treatment for chronic pain. These interfaces link neural sensors with device outputs to provide temporally precise stimulation. We discuss challenges and trends of state-of-the-art neural interfaces for treating pain in animal models and human pilot trials.

Central Neuropathic Pain

ABSTRACT OBJECTIVE This article provides an approach to the assessment, diagnosis, and treatment of central neuropathic pain. LATEST DEVELOPMENTS Recent studies of the pathophysiology of central neuropathic pain, including evidence of changes in the expression of voltage-gated sodium channels and N-methyl-d-aspartate (NMDA) receptors, may provide the basis for new therapies. Other areas of current research include the role of cannabinoid-receptor activity and microglial cell activation in various animal models of central neuropathic pain. New observations regarding changes in primary afferent neuronal activity in central neuropathic pain and the preliminary observation that peripheral nerve blocks may relieve pain due to central neuropathic etiologies provide new insights into both the mechanism and treatment of central neuropathic pain. ESSENTIAL POINTS In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. A multimodal, individualized approach to the management of central neuropathic pain is necessary to optimize pain relief and may require multiple treatment trials to achieve the best outcome.

Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.

Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons.

Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we found that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs. Disruption of OMDs potentiated action potential firing in nociceptor DRG neurons and facilitated the opening of native hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels. This increased neuronal firing is partially due to an increased open probability and altered gating kinetics of HCN channels. The gating effect on HCN channels was likely due to a direct modulation of their voltage sensors by OMDs. In animal models of neuropathic pain, we observed reduced OMD size and a loss of HCN channel localization within OMDs. Additionally, cholesterol supplementation inhibited HCN channels and reduced neuronal hyperexcitability in pain models. These findings suggest that disturbances in lipid nanodomains play a critical role in regulating HCN channels within nociceptor DRG neurons, influencing pain modulation.

A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.

Genetic studies have identified the voltage-gated sodium channel 1.7 (Nav1.7) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single-domain antibodies (VHHs) are developed against the human Nav1.7 (hNav1.7) using a novel antigen presentation strategy. A 70 amino-acid peptide from the hNav1.7 protein is identified as a target antigen. A recombinant version of this peptide is grafted into the complementarity determining region 3 (CDR3) loop of an inert VHH in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one VHH able to i) bind hNav1.7, ii) slow the deactivation of hNav1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This VHH exhibits the potential to be developed as a therapeutic capable of suppressing pain. This novel antigen presentation strategy can be applied to develop biologics against other difficult targets such as ion channels, transporters and GPCRs.

BMP10 accelerated spinal astrocytic activation in neuropathic pain via ALK2/smad1/5/8 signaling.

Astrocytic activation in the spinal dorsal horn contributes to the central sensitization of neuropathic pain. Bone morphogenetic protein (BMP) 10, one of the BMPs highly expressed in the central nervous system, has been demonstrated to have an accelerated effect on astrocytic activation. This study aimed to investigate the functional effects of BMP10 on the activation of astrocytes in the spinal dorsal horn of animal model of neuropathic pain and to explore potential mechanisms involved in this process. A neuropathic pain mice model was established using the spared nerve injury (SNI). Western blot analysis was performed to detect the expressional levels of BMP10, activin receptor-like receptor 2 (ALK2), Smad1/5/8, phosphorylated Smad1/5/8, and glial fibrillary acidic protein (GFAP). Immunofluorescence staining was used to detect BMP10, ALK2, and GFAP distribution and expression. The behavioral changes in mice were evaluated using paw withdrawal threshold (PWT), thermal withdrawal latency (TWL), and open field test (OFT). The BMP10 siRNA, Smad1 siRNA, BMP10 peptide, and ALK2-IN-2 (ALK2 inhibitor) were intrathecally administrated to mice. A model of lipopolysaccharide (LPS)-stimulated astrocytes was established to investigate the effect of Smad1. The transfection efficiency of siRNAs was detected by western blot and qRT-PCR analysis. BMP10 levels were increased in the L4-6 ipsilateral spinal dorsal horn of SNI mice and particularly elevated in astrocytes. Consistently, GFAP and phosphorylated Smad1/5/8 were upregulated in the L4-6 ipsilateral spinal dorsal horn after SNI, indicating the activation of astrocytes and Smad1/5/8 signaling. An intrathecal injection of BMP10 siRNA abrogated pain hypersensitivity and astrocytic activation in SNI mice. In addition, intrathecal administration of BMP10 peptide evoked pain hypersensitivity and astrocytic activation in normal mice, and this action was reversed by inhibiting the ALK2. Furthermore, targeting Smad1 in vitro with the help of siRNA inhibited the activation of astrocytes induced by LPS. Finally, targeting Smad1 abrogated BMP10-induced hypersensitivity and activation of astrocytes. These findings indicate that the BMP10/ALK2/Smad1/5/8 axis plays a key role in pain hypersensitivity after peripheral nerve injury, which indicates its stimulative ability toward astrocytes.

Local synthesis of estradiol in the rostral ventromedial medulla protects against widespread muscle pain in male mice.

Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ER), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signaling alters GABA receptor and transporter expression, we examined if removal of testosterone in males would decrease mRNA expression of GABA receptor subunits and vesicular GABA transporter (VGAT). However, there were no differences in mRNA expression of GABA receptor subunits of VGAT between gonadectomized and sham control males. Lastly, we used RNAscope to determine expression of ER-α in the RVM and show expression in inhibitory (VGAT+), serotonergic (tryptophan hydroxylase 2+), and μ-opioid receptor expressing (MOR+) cells. In conclusion, testosterone protects males from development of widespread hyperalgesia through aromatization to estradiol and activation of ER-α which is widely expressed in multiple cell types in the RVM.Significance Statement This study's findings reveal, for the first time, that testosterone protects males from development of widespread muscle hyperalgesia through aromatization to estradiol and activation of ER-α within the RVM. The findings also show, for the first time, ER-α expression in the RVM in male mice, and the distribution patterns of this expression among multiple cell types. Thus, together our data suggest a unique endogenous mechanism in the RVM for protection against widespread pain in males only.

Translational evaluation of Gelsectan® effects on gut barrier dysfunction and visceral pain in animal models and irritable bowel syndrome with diarrhoea.

Gelsectan® is a formulation of xyloglucan (XG), pea protein, grape seed extract (PPGS) and xylo-oligosaccharides (XOS). Our aim was to examine the effect of Gelsectan® on rectal sensitivity in an animal model, abdominal pain in irritable bowel syndrome with diarrhoea (IBS-D) subjects and intestinal permeability in both conditions. Animals: Wistar rats received gavage with XOS, XG+PPGS or XG+PPGS+XOS, as a single dose or for 7days before a partial restraint stress (PRS). Visceromotor response to rectal distension and total gut paracellular permeability to 51Cr-EDTA were assessed. Humans: IBS-D and control patients were involved. After initial colonoscopy with biopsy sampling Gelsectan® was administered to IBS-D patients for 12weeks. Stool count and pain scores were documented. After treatment, colonoscopy was repeated. The permeability of biopsy samples was measured in Ussing-chambers. Adherent mucus layer, Muc-2 expression as well as TNFα, Interferon IFNγ were evaluated by histology/immunohistochemistry and ELISA assays, respectively. Animal studies: In control rats, PRS significantly increased visceromotor response as well as gut paracellular permeability. Single dose administration of XG+PPGS+XOS failed to reverse PRS, but 7days of oral treatment reversed PRS-induced rectal hypersensitivity and gut hyperpermeability. Human studies: Gelsectan® treatment significantly reduced and abdominal pain. Intestinal permeability in IBS-D patients was elevated compared with controls, Gelsectan® restored permeability in the ascendent colon. Periodic acid-Schiff-stained mucus layer was significantly thinner in IBS-D patients compared with controls, In both segments, mucus thickness and the proportion of Muc-2 positive cells were not affected by Gelsectan® treatment. IFNγ tissue level in the sigmoid colon shows modest mucosal inflammation in IBS-D. Gelsectan® prevented rectal hypersensitivity in rats, abdominal pain in human and intestinal hyperpermeability in rat and human studies respectively. These effects involve restoration of gut permeability. Based on this translational study, Gelsectan® can be considered as an effective therapy for IBS-D symptoms.

THC Vapor Inhalation Attenuates Hyperalgesia in Rats Using a Chronic Inflammatory Pain Model

Humans use cannabinoid drugs to alleviate pain. As cannabis and cannabinoids are legalized in the United States for medicinal and recreational use, it has become critical to determine the potential utilities and harms of cannabinoid drugs in individuals living with chronic pain. Here, we tested the effects of repeated ∆9-tetrahydrocannabinol (THC) vapor inhalation on thermal nociception and mechanical sensitivity, in adult male and female Wistar rats using a chronic inflammatory pain model (ie, treated with complete Freund’s adjuvant [CFA]). We report that repeated THC vapor inhalation rescues thermal hyperalgesia in males and females treated with CFA and also reduces mechanical hypersensitivity in CFA males but not females. Many of the antihyperalgesic effects of chronic THC vapor were still observable 24 hours after cessation of the last THC exposure. We also report plasma levels of THC and its major metabolites, some of which are cannabinoid type-1 receptor agonists, after the first and tenth days of THC vapor inhalation. Finally, we report that systemic administration of the cannabinoid type-1 receptor inverse agonist AM251 (1 mg/kg, I.P.) blocks the antihyperalgesic effects of THC vapor in males and females. These data provide a foundation for future work that will explore the cells and circuits underlying the antihyperalgesic effects of THC vapor inhalation in individuals with chronic inflammatory pain. PerspectiveCannabinoids are thought to have potential utility in the treatment of chronic pain, but few animal studies have tested the effects of chronic THC or cannabis in animal models of chronic pain. We tested the effects of repeated THC vapor inhalation on chronic pain-related outcomes in male and female animals.