scholarly journals Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 417 ◽  
Author(s):  
Dinesh Thapa ◽  
Elizabeth A. Cairns ◽  
Anna-Maria Szczesniak ◽  
Pushkar M. Kulkarni ◽  
Alex J. Straiker ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Neutrophil Infiltration ◽  
Cannabinoid Receptor 1 ◽  
Corneal Injury ◽  
Combination Treatments ◽  
Pain Scores ◽  
Novel Approach

Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2−/− mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.

scholarly journals Beta-caryophyllene enhances wound healing through multiple routes

2019 ◽  
Author(s):  
Sachiko Koyama ◽  
Anna Purk ◽  
Manpreet Kaur ◽  
Helena A. Soini ◽  
Milos V. Novotny ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Cell Migration ◽  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Regulated Gene Expression ◽  
The Impact ◽  
Injured Skin

AbstractBeta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices. Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses. We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization. The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta-caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene. Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.

Abstract 3481: A Novel Mechanism Contributing to End Organ Damage in Endotoxic Shock: Role of TRPV1

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Youping Wang ◽  
Donna H Wang
Keyword(s):  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Endotoxic Shock ◽  
Receptor Potential ◽  
Neutrophil Infiltration ◽  
Organ Damage ◽  
Systemic Hemodynamics ◽  
Transient Receptor Potential Vanilloid ◽  
Hepatocellular Injury ◽  
Trpv1 Channels

We previously showed that transient receptor potential vanilloid type 1 (TRPV1) channels play a vital role in the survival of animals during endotoxic shock. To examine effects of TRPV1 on systemic hemodynamics, inflammatory responses, and renal and liver function/damage during endotoxic shock, lipopolysaccharide (LPS, 10 mg/kg) was injected i.p. into wild type (WT) and TRPV1-null mutant (TRPV1 −/− ) mice. Mean arterial pressure (MAP, mmHg) measured with radiotelemetry in conscious mice were severely decreased 11 hours after LPS injection in WT and TRPV1 −/− mice, with no difference between the two strains (76±6 vs. 71±4, p>0.05). The serum levels of alanine aminotransferase (ALT, indicator of liver dysfunction, IU/L) or creatinine (indicator of renal dysfunction, mg/dL) were increased 6 and 24 h after LPS injection in WT and TRPV1 −/− mice, with a greater magnitude in the latter strain (ALT, 79±11 vs. 105±16; creatinine, 0.7±0.09 vs. 1.2±0.08, p<0.05). Serum cytokine (pg/ml) and chemokine (ng/ml) levels were higher 6 h after LPS injection in TRPV1 −/− compared to WT mice (TNF-α, 718±43 vs. 428±44; IL-1β, 736±39 vs. 420±46; KC, 100±8 vs. 60±7; MIP-2, 2.2±0.4 vs. 1.3±0.3, p<0.05). LPS-induced neutrophil infiltration (cells/mm 2 ) was greater in the kidney and liver in TRPV1 −/− than in WT mice (kidney, 93±6 vs. 38±4; liver, 247±13 vs. 156±12, p<0.05). VCAM-1 or ICAM-1 expression was increased 6 and 24 h after LPS injection in the kidney and liver in WT and TRPV1 −/− mice, with a greater magnitude in the latter strain (p<0.05). Renal glomerular hypercellularity and hepatocellular injury were apparent 24 h after LPS injection in WT and TRPV1 −/− mice, with greater cellular density or injury in the latter strain. These data demonstrate that deletion of TRPV1 had no effect on LPS-induced fall in MAP, but accelerated organ damage during endotoxic shock. Exaggerated organ damage was accompanied by increased inflammatory responses as evident by enhanced neutrophil infiltration, proinflammatory cytokine production, and adhesion molecule expression. These data indicate that activation of TRPV1 attenuates organ damage possibly via its anti-inflammatory action without affecting systemic hemodynamics during endotoxic shock.

Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

2020 ◽  
Vol 13 ◽  
Author(s):  
Ashif Iqubal ◽  
Musheer Ahmed ◽  
Mohammad Kashif Iqubal ◽  
Faheem Hyder Pottoo ◽  
Syed Ehtaishamul Haque
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Side Effects ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Neutrophil Infiltration ◽  
Matrix Metal ◽  
Mediators Of Inflammation ◽  
Major Player ◽  
Cord Injury

: Spinal cord injury (SCI) and associated pain and inflammation caused by the trauma or infection is one of the serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factor but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts,pericytes, Schwann cells, meningeal cells are the major player in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases and serotonin that stimulate nerve endings and manifests the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, until now, these compounds have been studied in preclinical models and shown promising results but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

scholarly journals Intracellular pools of DAG-activated TRPC3 channels are essential for TLR4 activation

2021 ◽  
Author(s):  
Javier Casas ◽  
Clara Meana ◽  
José Ramón López-López ◽  
Jesús Balsinde ◽  
María A. Balboa
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Receptor Potential ◽  
Central Component ◽  
Lps Challenge ◽  
Intracellular Sensing ◽  
Lipin 1 ◽  
Transient Receptor ◽  
Tlr4 Activation

ABSTRACTToll-like receptor 4, the receptor for bacterial lipopolysaccharide (LPS), drives inflammatory responses that protect against pathogens and boost the adaptive immunity. LPS responses are known to depend on calcium fluxes, but the molecular mechanisms involved are poorly understood. Here we present evidence that the transient receptor potential canonical channel 3 (TRPC3) is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this way TRPC3 participates in cytosolic Ca2+ elevations, TLR4 endocytosis, activation of inflammatory transcription factors and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol (DAG) generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells show reduced Ca2+ responses to LPS challenge. A cameleon indicator directed to the endoplasmic reticulum shows that this is the organelle from which TRPC3 mediates the Ca2+ release. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3.

scholarly journals L-type calcium channels and MAP kinase contribute to thyrotropin-releasing hormone-induced depolarization in thalamic paraventricular nucleus neurons

2016 ◽  
Vol 310 (11) ◽  
pp. R1120-R1127 ◽  
Author(s):  
Miloslav Kolaj ◽  
Li Zhang ◽  
Leo P. Renaud
Keyword(s):  
Transient Receptor Potential ◽  
Cannabinoid Receptor ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Receptor Potential ◽  
Thyrotropin Releasing Hormone ◽  
Induced Response ◽  
Inward Current ◽  
Releasing Hormone ◽  
Intracellular Ca

In rat paraventricular thalamic nucleus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances neuronal excitability via concurrent decrease in a G protein-coupled inwardly rectifying K (GIRK)-like conductance and opening of a cannabinoid receptor-sensitive transient receptor potential canonical (TRPC)-like conductance. Here, we investigated the calcium (Ca2+) contribution to the components of this TRH-induced response. TRH-induced membrane depolarization was reduced in the presence of intracellular BAPTA, also in media containing nominally zero [Ca2+]o, suggesting a critical role for both intracellular Ca2+ release and Ca2+ influx. TRH-induced inward current was unchanged by T-type Ca2+ channel blockade, but was decreased by blockade of high-voltage-activated Ca2+ channels (HVACCs). Both the pharmacologically isolated GIRK-like and the TRPC-like components of the TRH-induced response were decreased by nifedipine and increased by BayK8644, implying Ca2+ influx via L-type Ca2+ channels. Only the TRPC-like conductance was reduced by either thapsigargin or dantrolene, suggesting a role for ryanodine receptors and Ca2+-induced Ca2+ release in this component of the TRH-induced response. In pituitary and other cell lines, TRH stimulates MAPK. In PVT neurons, only the GIRK-like component of the TRH-induced current was selectively decreased in the presence of PD98059, a MAPK inhibitor. Collectively, the data imply that TRH-induced depolarization and inward current in PVT neurons involve both a dependency on extracellular Ca2+ influx via opening of L-type Ca2+ channels, a sensitivity of a TRPC-like component to intracellular Ca2+ release via ryanodine channels, and a modulation by MAPK of a GIRK-like conductance component.

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