RT Journal Article SR Electronic T1 Co-Administration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine’s Analgesic Effect on Incisional Pain in Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.118.252890 DO 10.1124/jpet.118.252890 A1 Saadet Inan A1 Toby K Eisenstein A1 Mia N Watson A1 Menahem Doura A1 Joseph J Meissler A1 Christopher S Tallarida A1 Xiaohong Chen A1 Ellen B Geller A1 Scott M Rawls A1 Alan Cowan A1 Martin W Adler YR 2018 UL http://jpet.aspetjournals.org/content/early/2018/09/24/jpet.118.252890.abstract AB Cross-desensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if co-administration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points post-surgery between 15 and 360 minutes and daily between 24 and 72 hours. Dose-response curves for morphine, maraviroc (a CCR5 antagonist) and AMD3100 (a CXCR4 antagonist) alone were established. While morphine significantly reduced pain in a time- and dose-dependent manner, maraviroc and AMD3100 had no effect by themselves. Co-administration of either maraviroc or AMD3100 with morphine significantly increased morphine's analgesic effect on incisional pain, shifting the dose-response curve to the left 2.31-fold and 1.8-fold, respectively. Co-administration of both CRAs with morphine significantly shifted the morphine dose-response curve to the left 3.3-fold. The effect of treatments on mRNA levels in the draining popliteal lymph node for a panel of chemokines and cytokines showed that message for many of these mediators was upregulated by the incision, and the combination of morphine with the CRAs markedly downregulated them. The data show that combining morphine with CRAs potentiates morphine's analgesic effect on incisional pain. Thus, the same analgesic effect of morphine alone can be achieved with lower doses of morphine when combined with CRAs. Using morphine in lower doses could reduce unwanted side effects and possibly block development of tolerance and dependence.