....Alterations in mice expressing sickle hemoglobin: modulation by cannabinoids..Alterações neuroquímicas em camundongos que expressam hemoglobina falciforme: modulação por canabinóides..Alteraciones en ratones que expresan hemoglobina falciforme....
*Divyanshoo R. Kohli,1 *Yunfang Li,1 Sergey G. Khasabov,2 Pankaj Gupta,3 Lois J. Kehl,4 Marna E. Ericson,5 Julia Nguyen,1 Vinita Gupta,6 Robert P. Hebbel,1 Donald A. Simone,2 and Kalpna Gupta1 1Vascular Biology Center, Division of Hematology, Oncology & Transplantation, Department of Medicine, and 2Department of Diagnostic & Biological Sciences, University of Minnesota, Minneapolis; 3Division of Hematology, Oncology & Transplantation, Department of Medicine, University of Minnesota and Veterans Administration Medical Center, Minneapolis; 4Minnesota Head and Neck Pain Clinic, St Paul; 5Department of Dermatology, University of Minnesota, Minneapolis; and 6Bio-Rad Laboratories, Hercules, CA
Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1, respectively) compared with control mice expressing human hemoglobin A (HbA-BERK), indicating deep/musculoskeletal and cutaneous hyperalgesia.
Peripheral nerves and blood vessels were structurally altered in BERK and hBERK1 skin, with decreased expression of opioid receptor and increased calcitonin gene-related peptide and substance P immunoreactivity. Activators of neuropathic and inflammatory pain (p38 mitogen-activated protein kinase, STAT3, and mitogen-activated protein kinase/extracellular signal-regulated kinase) showed increased phosphorylation, with accompanying increase in COX-2, interleukin-6, and Toll-like receptor 4 in the spinal cord of hBERK1 compared with HbA-BERK.
These neurochemical changes in the periphery and spinal cord may contribute to hyperalgesia in mice expressing HbS. In BERK and hBERK1, hyperalgesia was markedly attenuated by morphine and cannabinoid receptor agonist CP 55940. We show that mice expressing HbS exhibit characteristics of pain observed in sickle cell disease patients, and neurochemical changes suggestive of nociceptor and glial activation. Importantly, cannabinoids attenuate pain in mice expressing HbS. (Blood. 2010;116(3):456-465).
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