Dual dose-related effects evoked by CCL4 on thermal nociception after gene delivery or exogenous administration in mice
| Autor: | Sara González-Rodríguez, Ana Gutiérrez-Fernández, Ana Baamonde, Luis Menéndez, Mario García-Domínguez, Agustín Hidalgo, Ana Lastra, Alina Aguirre |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Nociception CCR2 Chemokine Hot Temperature CCL4 Pharmacology Biochemistry 03 medical and health sciences Mice 0302 clinical medicine medicine Animals CXCL13 Chemokine CCL4 Macrophage inflammatory protein biology Dose-Response Relationship Drug Chemistry Gene Transfer Techniques CXCL1 030104 developmental biology Hyperalgesia 030220 oncology & carcinogenesis biology.protein medicine.symptom |
| Zdroj: | Biochemical pharmacology. 175 |
| ISSN: | 1873-2968 |
| Popis: | 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 (Garcia-Dominguez 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. |
| Databáze: | OpenAIRE |
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