Coadministration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine’s Analgesic Effect on Incisional Pain in Rats

Abstract

Crossdesensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if coadministration 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 postsurgery 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. Coadministration of either maraviroc or AMD3100 with morphine significantly increased morphine's analgesic effect on incisional pain, shifting the dose-response curve to the left 2.3and 1.8-fold, respectively. Coadministration of both CRAs with morphine significantly shifted further the morphine doseresponse 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.

Blockade of CC Chemokine Receptor Type 3 Diminishes Pain and Enhances Opioid Analgesic Potency in a Model of Neuropathic Pain

“…Because of the significant changes in the levels of CCL7 and CCL11, the ligands of CCR3, the aforementioned receptor seems to be an interesting target for neuropathy treatment. Notably, blockade of other chemokine receptors in the CC family by their antagonists, e.g., CCR1 - J113863 ( 27 ), CCR2 - RS504393 ( 29 ), CCR4 - C021 ( 50 ), and CCR5 - maraviroc ( 31 , 61 ), beneficially modulates the changes observed during neuropathy, consistent with our previous reports ( 27 , 29 , 50 ). Therefore, we decided to use the CCR3 antagonist SB328437 to determine whether the blockade of this receptor would also be a beneficial pain treatment.…”

Opioid‐sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors

“…These results are summarized in Table . Similarly, previous report from our laboratory (Inan et al, ) showed that combining sub‐analgesic doses of morphine with chemokine receptor antagonists could provide maximal analgesia in a rat model of incisional pain.…”

Bidirectional Regulation of Opioid and Chemokine Function

“…Taken together, these studies suggest an extensive degree of regulation of the function of opioid receptors that is mediated by chemokine receptors. A very recent report shows that the co-administration of chemokine receptor antagonists potentiates the capacity of morphine to generate an analgesic response in a model of inflammatory pain (132). These results suggest that the results on heterologous desensitization can be clinically translated by interfering with the chemokine-mediated desensitization of MOP function in conditions involving inflammatory pain.…”

“…Pain is one of the cardinal signs of inflammation, and the mechanisms that are responsible for the increase in sensitivity to pain are complex. Elevated levels of pro-inflammatory chemokines have been measured at sites of chronic inflammation, and these chemokines contribute to the increase in pain sensitivity (132). Based on the knowledge of cross-talk between chemokine and opioid receptors, studies have been conducted to determine the capacity of various pro-inflammatory chemokines to induce heterologous desensitization of opioid receptors.…”