Dual dose-related effects evoked by CCL4 on thermal nociception after gene delivery or exogenous administration in mice.

Abstract

As recently described, the administration of extremely low doses (pg/kg) of CCL4 (Macrophage inflammatory protein 1β, MIP-1β) can induce antinociceptive effects in mice (García-Domínguez et al., 2019b). We describe here that hydrodynamic delivery of a plasmid containing CCL4 cDNA provokes a biphasic response consisting in an initial thermal hyperalgesic reaction for 8 days followed by analgesia at days 10-12, being both responses blocked after the administration of the CCR5 antagonist DAPTA. Both the luminiscence evoked in liver after the administration of a plasmid containing CCL4 and luciferase cDNAs and the hepatic concentration of CCL4 measured by ELISA were maximal 4 days after plasmid administration and markedly diminished at day 10. A dose-effect curve including a wide dose range of exogenous CCL4 revealed thermal analgesia after the administration of 10-100 pg/kg whereas 1000 times higher doses (30-100 ng/kg) induced, instead, thermal hyperalgesia inhibited by DAPTA. This hyperalgesia was absent in mice with reduced white blood cells after cyclophosphamide treatment, thus supporting the involvement of circulating leukocytes. A multiarray bioluminescent assay revealed increased plasma levels of IL-1α, CCL2, CXCL1, CXCL13, IL-16 and TIMP-1 in mice treated with 100 ng/kg of CCL4. The hyperalgesic response evoked by CCL4 was prevented by IL-1R, CXCR2 or CCR2 antagonists or by the neutralization of CXCL13 or IL-16, but not TIMP-1, with selective antibodies. The administration of the anti-IL-16 antibody was the unique treatment able to convert hyperalgesia evoked by 100 ng/kg of CCL4 in an analgesic effect. The ability of IL-16 to evoke hypernociception was confirmed by studying the response to its exogenous administration (10-30 ng/kg). In summary, the present results demonstrate that CCL4 induces a dual modulation of nociception and describe some mechanisms involved in the hyperalgesic response evoked by this chemokine.

• Authors: Alina Aguirre, Sara González-Rodríguez, Mario García-Domínguez, Ana Lastra, Ana Gutiérrez-Fernández, Agustín Hidalgo, Luis Menéndez, Ana Baamonde
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 175 Pg. 113903 (05 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32156658 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Ccl4 protein, mouse
• Chemokine CCL4

Topics

• Animals
• Chemokine CCL4 (administration & dosage, genetics)
• Dose-Response Relationship, Drug
• Gene Transfer Techniques
• Hot Temperature (adverse effects)
• Hyperalgesia (drug therapy, genetics)
• Male
• Mice
• Nociception (drug effects, physiology)