Background and Purpose: Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization. Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory. The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB₁R) and cannabinoid 2 (CB₂R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia. Methods: Corneal hyperalgesia (increased pain response) was generated using chemical cauterization of the corneal epithelium in wild-type (WT) and CB₂R knockout (CB₂R^−/−) mice. Cauterized eyes were treated topically with the phytocannabinoids Δ⁸-tetrahydrocannabinol (Δ⁸THC) or cannabidiol (CBD), or the CBD derivative HU-308, in the presence or absence of the CB₁R antagonist AM251 (2.0 mg/kg i.p.), or the 5-HT_1A receptor antagonist WAY100635 (1 mg/kg i.p.). Behavioral pain responses to a topical capsaicin challenge at 6 h postinjury were quantified from video recordings. Mice were euthanized at 6 and 12 h postcorneal injury for immunohistochemical analysis to quantify corneal neutrophil infiltration. Results: Corneal cauterization resulted in hyperalgesia to capsaicin at 6 h postinjury compared to sham control eyes. Neutrophil infiltration, indicative of inflammation, was apparent at 6 and 12 h postinjury in WT mice. Application of Δ⁸THC, CBD, and HU-308 reduced the pain score and neutrophil infiltration in WT mice. The antinociceptive and anti-inflammatory actions of Δ⁸THC, but not CBD, were blocked by the CB₁R antagonist AM251, but were still apparent, for both cannabinoids, in CB₂R^−/− mice. However, the antinociceptive and anti-inflammatory actions of HU-308 were absent in the CB₂R^−/− mice. The antinociceptive and anti-inflammatory effects of CBD were blocked by the 5-HT_1A antagonist WAY100635. Conclusion: Topical cannabinoids reduce corneal hyperalgesia and inflammation. The antinociceptive and anti-inflammatory effects of Δ⁸THC are mediated primarily via CB₁R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT_1A receptors and CB₂Rs, respectively. Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.

Background and purpose: Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB₁receptors (CB₁) are present in TM and cannabinoid administration decreases IOP. CB₁signalling was investigated in a cell line derived from human TM (hTM).Experimental approach: CB₁signalling was investigated using ratiometric Ca²⁺imaging, western blotting and infrared In‐Cell Western analysis.Key results: WIN55212‐2, a synthetic aminoalkylindole cannabinoid receptor agonist (10–100 μM) increased intracellular Ca²⁺in hTM cells. WIN55,212‐2‐mediated Ca²⁺increases were blocked by AM251, a CB₁antagonist, but were unaffected by the CB₂antagonist, AM630. The WIN55,212‐2‐mediated increase in [Ca²⁺]_iwas pertussis toxin (PTX)‐insensitive, therefore, independent of G_i/ocoupling, but was attenuated by a dominant negative Gα_q/11subunit, implicating a G_q/11signalling pathway. The increase in [Ca²⁺]_iwas dependent upon PLC activation and mobilization of intracellular Ca²⁺stores. A PTX‐sensitive increase in extracellular signal‐regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212‐2, indicative of a G_i/osignalling pathway. CB₁‐G_q/11coupling to activate PLC‐dependent increases in Ca²⁺appeared to be specific to WIN55,212‐2 and were not observed with other CB₁agonists, including CP55,940 and methanandamide. CP55940 produced PTX‐sensitive increases in [Ca²⁺]_iat concentrations ≥15 μM, and PTX‐sensitive increases in ERK1/2 phosphorylation.Conclusions and implications: This study demonstrates that endogenous CB₁couples to both G_q/11and G_i/oin hTM cells in an agonist‐dependent manner. Cannabinoid activation of multiple CB₁signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.British Journal of Pharmacology(2007)152, 1111–1120; doi:10.1038/sj.bjp.0707495; published online 8 October 2007

Introduction: Cannabinoid receptor 2 (CB2R) expression is upregulated during sepsis. However, there are conflicting results regarding the effects of CB2R modulation in the hyperinflammatory phase of the disease. The aim of this study was therefore to investigate the effects of CB2R manipulation on leukocyte activation within the intestinal microcirculation in two acute experimental sepsis models. Methods: In the endotoxemia model we studied four groups of Lewis rats: controls, lipopolysaccharide (LPS), LPS + CB2R agonist HU308 (2.5 mg/kg), and LPS + CB2R antagonist AM630 (2.5 mg/kg). In the colon ascendens stent peritonitis (CASP)-induced sepsis model we also studied four groups: sham group, CASP and CASP + CB2R agonist (HU308, 2.5 or 10 mg/kg). Intravital microscopy was performed 2 hours following LPS/placebo administration or 16 hours following CASP/sham surgery to quantify intestinal leukocyte recruitment. Additionally, hemodynamic monitoring, histological examinations and measurements of inflammatory mediators were performed. Results: HU308 administration significantly reduced intestinal leukocyte adhesion in both acute sepsis models. The systemic levels of inflammatory mediators were significantly reduced by 10 mg/kg HU308 treatment in CASP animals. Conclusion: CB2R activation reduces leukocyte activation and systemic release of inflammatory mediators in acute experimental sepsis. Drugs targeting the CB2R pathway may have therapeutic potential in sepsis.

This review examines the function of calcium-activated chloride currents (ICl(Ca)) in the retina with an emphasis on their physiological role in photoreceptors. Although found in a variety of neurons and glial cells of the retina, ICl(Ca) has been most prominently studied in cones, where it activates in response to depolarization-evoked Ca2+ influx. The slow and complex gating kinetics of the chloride current have been considered to reflect the changing submembrane concentration of intracellular calcium. It is likely that the role of ICl(Ca) is to stabilize the membrane potential of cones during synaptic activity and presynaptic Ca channel modulation. Several candidates in the molecular identification of the channel have been put forward but the issue remains unresolved.