The Systemic Administration of the Chemokine CCL1 Evokes Thermal Analgesia in Mice Through the Activation of the Endocannabinoid System

• Published in: Cellular and molecular neurobiology 2019-11, Vol.39 (8), p.1115-1124
• Main Authors: García-Domínguez, Mario, Aguirre, Alina, Lastra, Ana, Hidalgo, Agustín, Baamonde, Ana, Menéndez, Luis
• Format: Article
• Language: English
• Subjects: 2-Arachidonoylglycerol; Analgesia; Analgesics; Analgesics - pharmacology; Animals; Arachidonic Acids - metabolism; Biomedical and Life Sciences; Biomedicine; Cannabinoids; CCR8 protein; Cell Biology; Chemokine CCL1 - administration & dosage; Chemokines; Cyclophosphamide; Endocannabinoid system; Endocannabinoids - metabolism; Enzyme-linked immunosorbent assay; Fos protein; Glycerides - metabolism; Leukocytes; Leukocytes - drug effects; Leukocytes - metabolism; Lumbar Vertebrae - drug effects; Lumbar Vertebrae - metabolism; Male; Mice; Models, Biological; Naloxone; Neurobiology; Neurons - drug effects; Neurons - metabolism; Neurosciences; Opioid receptors; Original Research; Pain perception; Proto-Oncogene Proteins c-fos - metabolism; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Receptors, CCR8 - metabolism; Spinal cord; Temperature
• ISSN: 0272-4340; 1573-6830; 1573-6830
• DOI: 10.1007/s10571-019-00706-3

Apart from its involvement in immune functions, the chemokine CCL1 can participate in the modulation of nociceptive processing. Previous studies have demonstrated the hypernociceptive effect produced by CCL1 in the spinal cord, but its possible action on peripheral nociception has not yet been characterized. We describe here that the subcutaneous administration of CCL1 (1–10 µg/kg) produces dose-dependent and long-lasting increases in thermal withdrawal latencies measured by the unilateral hot plate test in mice. The antinociceptive nature of this effect is further supported by the reduction of spinal neurons expressing Fos protein in response to a noxious thermal stimulus observed after the administration of 10 µg/kg of CCL1. CCL1-induced antinociception was inhibited after systemic, but not spinal administration of the selective antagonist R243 (0.1–1 mg/kg), demonstrating the participation of peripheral CCR8 receptors. The absence of this analgesic effect in mice treated with a dose of cyclophosphamide that produces a drastic depletion of leukocytes suggests its dependency on white blood cells. Furthermore, whereas the antinociceptive effect of CCL1 was unaffected after the treatment with either the antagonist of opioid receptors naloxone or the cannabinoid type 1 receptor blocker AM251, it was dose-dependently inhibited after the administration of the CB2 receptor antagonist SR144528 (0.1-1 mg/kg). The detection by ELISA of an increased presence of the endocannabinoid 2-arachidonoylglycerol after the administration of an analgesic dose of CCL1 supports the notion that CCL1 can evoke thermal analgesia through the release of this endocannabinoid from circulating leukocytes.