LY2828360 / Eli Lilly - LARVOL DELTA

Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain. (PubMed, Cannabis Cannabinoid Res) - "The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed...Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested...The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition...Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach."

Journal • Pain

The cannabinoid CB2 agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats. (PubMed, Neuropharmacology) - "Here we show that LY2828360 (3 and 10 mg/kg i.p.), administered acutely, reversed paclitaxel-induced mechanical hypersensitivity in male rats. LY2828360 (3 mg/kg i.p.) did not produce preference or aversion in the conditioned place preference (CPP) test in rats when administered alone but blocked CPP to morphine (6 mg/kg i.p.). Lastly, LY2828360 (3 mg/kg i.p.) did not alter the acquisition of i.v. morphine self-administration under fixed ratio 1 (FR1) and 3 (FR3) or motivation to work for morphine under a progressive ratio (PR) schedule of reinforcement."

Journal • Preclinical • Immunology • Neuralgia • Pain

Cannabinoid receptor 1 and 2 are involved in HIV-related neuropathic pain model (IASP 2024) - "In mice model, mice received intrathecal gp120 with morphine once a day for 3 days...Either CB1 receptor agonist ACEA or CB2 receptor agonist LY2828360 was injected intrathecally... Current preliminary data suggest that both CB1/2 agonists produced analgesia, but chronic ACEA for induced antinociceptive tolerance in HIV-related neuropathic pain model. We will continue to study the molecular mechanisms of HIV-related pain.No Conflict(s) of Interest in the research."

Human Immunodeficiency Virus • Infectious Disease • Neuralgia • Pain

Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance. (PubMed, Biomed Pharmacother) - "Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications."

Journal • Oncology • Pain • CX3CR1

Interacting with luteinizing hormone receptor provides a new elucidation of the mechanism of anti-androgenicity of bisphenol S. (PubMed, Chemosphere) - "BPS exposure decreased the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2), and the inhibitory effects of BPS on testosterone content and steroidogenic gene expression were blocked by ERK1/2 agonist LY2828360, suggesting that ERK1/2 signaling pathway mediates the inhibitory effects of BPS on androgen synthesis. BPS mainly accumulated on the cell membrane, impermeable BPS-bovine serum albumin exposure still inhibited androgen synthesis, BPS interacted with rat luteinizing hormone receptor (LHR) via formation of hydrogen bonds in the transmembrane region, and the inhibitory effects of BPS on ERK1/2 phosphorylation were blocked by luteinizing hormone (the natural agonist of LHR), indicating that LHR located on the cell membrane is the target of action of BPS. This paper provides a new elucidation of the mechanism of anti-androgenicity of BPS, especially for the non-genomic pathways."

Journal

Tlr4, lcn2, and cb1/2 are involved in HIV-related neuropathic pain model in mice (Neuroscience 2023) - "Neuropathic pain was induced by repeated intrathecal administration of recombinant HIV glycoprotein gp120 with morphine (gp120/M) in mice. Either CB1 receptor agonist ACEA or CB2 receptor agonist LY2828360 suppressed neuropathic pain in mice. Current preliminary data suggest that TLR4, LCN2, and CB1/2 are involved in HIV-related neuropathic pain model in mice."

Preclinical • CNS Disorders • Neuralgia • Pain • TLR4

Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain. (PubMed, Neuropharmacology) - "The anti-allodynic efficacy of LY2828360 was absent in conditional KO mice lacking CB receptors in peripheral sensory neurons (Advillin; CB). Lastly, qRT-PCR analyses revealed that LY2828360 reduced carrageenan-induced increases in IL-1β and IL-10 mRNA in paw skin. Our results provide evidence that LY2828360 suppresses inflammatory nociception in mice through a neuronal CB-dependent mechanism that requires peripheral sensory neuron CB receptors and suggest that the clinical applications of LY2828360 as an anti-hyperalgesic agent should be re-evaluated."

Journal • Preclinical • Inflammation • Neuralgia • Pain • IL10 • IL1B

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy. (PubMed, Pharmacol Res) - "Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillin;CB2 mice, which exhibited robust ddC-induced neuropathy. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists."

Journal • Preclinical • Human Immunodeficiency Virus • Immunology • Infectious Disease • Neuralgia • Pain • Peripheral Neuropathic Pain • CCL2 • IL1B • TNFA

Synthetic CB1 agonists induce respiratory depression in awake adult mice - a potential role for beta arrestin (Neuroscience 2022) - "Our lab previously reported that LY2828360, a G protein-biased cannabinoid receptor type 2 (CB2) agonist, lacked intrinsic effects on respiratory parameters and attenuated fentanyl-induced respiratory depression. These results suggest that CB1 receptors are expressed in CNS neurons that are responsible for the regulation of respiratory function. The susceptibility of these neurons to exogenous CB1 agonists may explain clinical observations of respiratory depression after the administration of synthetic cannabinoid drugs."

Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry • ARRB1

A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse. (PubMed, Pain) - "Structurally distinct CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB2EGFP reporter mice with established neuropathy. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception."

Journal • Preclinical • Oncology • Pain • CCL2 • IL10 • TNFA

Cannabinoid CB Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression. (PubMed, Cannabis Cannabinoid Res) - "Our laboratory recently reported that the G protein-biased CB cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. Moreover, the CB agonist, administered alone, did not alter respiration. Our findings suggest that the CB cannabinoid agonist LY2828360 may provide CB-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

Tubular human brain organoids to model microglia-mediated neuroinflammation. (PubMed, Lab Chip) - "We found isogenic microglia were activated after exposure to an opioid receptor agonist (DAMGO) and transformed back to the homeostatic status with further treatment by a cannabinoid receptor 2 (CB2) agonist (LY2828360)...Our tubular organoid device is simple, versatile, inexpensive, easy-to-use, and compatible with multiwell-plates, so it can be widely used in common research and clinical laboratory settings. This technology can be broadly used for basic and translational applications in inflammatory diseases including substance use disorders, neural diseases, autoimmune disorders, and infectious diseases."

Journal • CNS Disorders • Immunology • Infectious Disease • Inflammation