|J Pain. 2018 May 2. pii: S1526-5900(18)30159-7. doi: 10.1016/j.jpain.2018.04.009. [Epub ahead of print]|
Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice.
Zhang M1, Dong L1, Zou H2, Li J3, Li Q1, Wang G4, Li H5.
Department of Anesthesiology, Cancer Hospital of Harbin Medical University.
Department of Pain, Cancer Hospital of Harbin Medical University.
Department of Statistics, Harbin Medical University.
Department of Anesthesiology, Cancer Hospital of Harbin Medical University; Pain Research Institute of Heilongjiang Academy of Medical Sciences. Electronic address: firstname.lastname@example.org.
Department of neurobiology, Harbin Medical University. Electronic address: email@example.com.
Morphine is a potent opioid analgesic used to alleviate moderate or severe pain but the development of drug tolerance and dependence limits its use in pain management. Previous studies showed that cannabinoid type 2 (CB2) receptor ligands may modulate opioid effects. However, there is no report of the effect of CB2 receptor agonist on acute morphine tolerance and physical dependence. We therefore investigated the effect of a CB2 receptor agonist (AM1241) on morphine-induced morphine tolerance and physical dependence in mice. Repeated coadministration of AM1241 (1 or 3mg/kg, intraperitoneally) and morphine (10mg/kg, subcutaneously) for 7 days increased mechanical paw withdrawal threshold in mice as measured by the von Frey filament test, and 3mg/kg AM1241 in combination with morphine increased thermal paw withdrawal latency as measured by the hot-plate test. Combination with 3 mg/kg AM1241 and morphine increased acute morphine antinociception. Coadministration of 1 or 3 mg/kg AM1241 and morphine reduced acute morphine tolerance, and 3 mg/kg AM1241 reduced chronic morphine tolerance. Coadministration of 1 or 3 mg/kg AM1241 and morphine reduced naloxone-precipitated withdrawal jumping, but not diarrhea. Coadministration of AM1241 and morphine did not inhibit spontaneous locomotor activity. Pretreatment with 3 mg/kg AM1241 reduced the chronic morphine-induced Iba1 expression in spinal cord. Coadministration of AM1241 (3 mg/kg) reduced the production of IL-1ß, TNF-aand IL-6 induced by chronic and acute morphine treatment. Our findings suggest that coadministration of the CB2 receptor agonist and morphine could increase morphine antinociception and reduce morphine tolerance and physical dependence in mice.
Combination of a CB2 agonist and morphine may provide a new strategy for better treatment of acute and chronic pain, and prevention of opioid tolerance and dependence. This may also provide a clue for the treatment of opioid tolerance and dependence in clinic.
CNS Drugs. 2018 May 7. doi: 10.1007/s40263-018-0515-7. [Epub ahead of print]
Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer's Disease.
Del Cerro P1, Alquézar C1, Bartolomé F1,2,3, González-Naranjo P4, Pérez C4, Carro E2,3, Páez JA4, Campillo NE5, Martín-Requero Á6,7.
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
Neurodegenerative Disorders Group, Instituto de Investigacion Hospital, 12 de Octubre, Madrid, Spain.
CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Instituto de Química Médica (CSIC), Madrid, Spain.
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain. firstname.lastname@example.org.
Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. email@example.com.
CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. firstname.lastname@example.org.
Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.
The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer's disease, contributing to the instigation of the disease.
Lymphoblastoid cell lines from patients with Alzheimer's disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in ß-amyloid-treated neuronal cells.
We report here that PGN33 normalized the increased proliferative activity of Alzheimer's disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented ß-amyloid-induced cell death in neuronal cells.
Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.