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Salvador Sierra San Nicolas
Icahn School of Medicine
Biography :

Salvador Sierra San Nicolas MD, PhD is currently a Postdoctoral Fellow in Icahn School of Medicine at Mount Sinai, Department of Pharmacological Sciences.

Abstract :

Summary: Opioid and cannabinoid receptor function is modulated by multiple mechanisms and both receptors are critical to a number of physiological processes in health and disease including nociception. We have previously reported that CB1 and delta receptors associate to form heteromers that exhibit distinct pharmacological properties and disease-specific dysregulation including during neuropathic pain. Hence these receptors have been posited as desired targets for pain relief; however, the in vivo consequences of heteromer signaling or their specific location along the pain circuit is not fully explored. Towards this end, we have initiated studies using the cancer chemotherapy drug paclitaxel-induced allodynia (mechanical allodynia) as a model of neuropathic pain. Mice (C57BL/6J mice; 10/group) were treated with vehicle or paclitaxel on alternate days (cumulative doses 16 mg/kg); paclitaxel-induced (mechanical) allodynia was assessed on days 0, 4, 7 and 15. On day 16, tissues were collected and levels of CB1 and delta receptors in spinal cord and brain regions were assessed using a receptor-selective or heteromer-selective antibodies and proximity based techniques. We find a significant increase in the abundance of CB1-delta receptor heteromers in the spinal cord of animals with allodynia. This interaction was found in the soma and presynaptic location in neurons as well as astrocytes but not in microglia. In order to assess the clinical relevance of the CB1-DOR heteromer we treated the animals with a low dose of CB1R agonist, DOR agonist or the combination. The combination of low doses of both agonists have a synergistic effect compared to each ligand alone. Currently we are working on the presence of this interaction in human samples of spinal cord to confirm these findings in patients treated with paclitaxel. Together, these results suggest an important role for pain in orchestrating the regulation of CB1-DOR heteromer levels and signaling in specific pain related pathways.

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