Details

Autor(en) / Beteiligte

• Inan, Saadet
• Chen, Xiaohong
• Eisenstein, Eric M.
• Meissler, Joseph J.
• Geller, Ellen B.
• Tallarida, Christopher
• Watson, Mia
• Doura, Menahem
• Barrett, James E.
• Cowan, Alan
• Rawls, Scott M.
• Adler, Martin W.
• Eisenstein, Toby K.

Titel

Chemokine receptor antagonists enhance morphine's antinociceptive effect but not respiratory depression

Ist Teil von

• Life sciences (1973), 2021-11, Vol.285, p.120014, Article 120014

Ort / Verlag

New York: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• We have shown that chemokines injected into the periaqueductal gray region of the brain blocks opioid-induced analgesia in the rat cold-water tail flick test (CWTF). The present experiments tested whether chemokine receptor antagonists (CRAs), in combination with sub-analgesic doses of morphine, would provide maximal analgesia in the CWTF test and the mouse formalin pain assay. The effect of CRAs on respiratory depression was also evaluated. One, two or four CRAs (AMD3100/CXCR4, maraviroc/CCR5, RS504393/CCR2 orAZD8797/CX3CR1) were used in combination with sub-analgesic doses of morphine, all given systemically. Pain was assessed using the rat CWTF test or formalin injection into the paw of mice scored by licking. Respiration and oxygen saturation were measured in rats using a MouseOX® Plus – pulse oximeter. In the CWTF test, a sub-maximal dose of morphine in combination with maraviroc alone, maraviroc plus AMD3100, or with the four chemokine receptor antagonists, produced synergistic increases in antinociception. In the formalin test, the combination of four CRAs plus a sub-maximal dose of morphine resulted in increased antinociception in both male and female mice. AMD3100 had an additive effect with morphine in both sexes. Coadministration of CRAs with morphine did not potentiate the opioid respiratory depressive effect. These results support the conclusion that combinations of CRAs can increase the potency of sub-analgesic doses of morphine analgesia without increasing respiratory depression. The results support an “opioid sparing” strategy for alleviation of pain using reduced doses of opioids in combination with CRAs to achieve maximal analgesia. •Chemokine receptor antagonists (CRAs) enhanced morphine's antinociceptive effect.•The CRAs that were tested did not have intrinsic antinociceptive activity.•Multiple CRAs were more potent than one CRA in enhancing morphine analgesia.•Combining CRAs + morphine did not increase morphine-induced respiratory depression.