PDGF-β-inhibiting activity of imatinib also reverses established tolerance.

Platelet-derived growth factor receptor-β (PDGFR-β) inhibitors such as the anticancer drug imatinib (Gleevec) can prevent or reverse tolerance to morphine analgesia, scientists claim.  A team at the University of Texas–MD Anderson Cancer Center has found that morphine-treated rats administered with a formulation of imatinib that crosses the blood brain barrier don’t become tolerant to the pain-relieving effects of morphine. When administered to already morphine-tolerant animals, the imatinib formulation also reversed morphine tolerance.

Describing their findings in Nature Medicine, Howard B Gutstein, Ph.D., and colleagues report that tolerance to morphine was associated with PDGF-β activation by the drug, and release of PDGF subunit B. Imatinib effectively blocked PDGF-β activation, and so prevented morphine tolerance from developing. The researchers claim that given the widespread use of PDGF-β inhibitors, clinical translation of their findings “could reduce the suffering endured by individuals with intractable pain.”

 PDGFR is a receptor tyrosine kinase that plays a key role in modulating the func­tion of the N-methyl-D-aspartate receptor (NMDAR), which is known to have a mechanistic role in opioid tolerance. Unfortunately, studies evaluating NMDAR antagonists as an approach to blocking morphine tolerance either haven’t been effective in a clinical setting, or have exhibited neurotoxicity. Because the μ-opioid receptor (MOR) transactivates PDGFR-β and other receptor tyrosine kinases, the investigators tested whether blocking PDGFR-β might represent an alternative approach to preventing the development of opioid tolerance.

The tstarting point was the anticancer drug imatinib, which inhibits a number of tyroskine kinase enzymes, including PDGFR-β. The team reformulated the drug to improve its ability to cross the blood-brain barrier. Initial in vitro studies in MOR-transfected C6 glioma cells confirmed that morphione administration led to rapid PDGFR-β phosphorylation and activation, but didn’t induce PDGFR-α phosphorylation.

The investigators then treated experimental rats intrathecally with morphine, imatinib, or both drugs, and collected and analysed spinal cords 40 minutes later.  Morphine was found to cause a 47% increase in PDGFR-β phospho­rylation in substnatia gelitinosa tissue, which was blocked by treatment with imatinib. In vivo, imatinib itself had no analgesic properties, and treatment with the drug didn’t change the analgesic potency of morphine. However, when imatinib was administered alongside morphine, the drug prevented the development of morphine tolerance. These tolerance-blocking and tolerance reversing abilities held even at the highest tolerated dose of morphine, and whether imatinib was administered intrathecally or subcutaneously.

Starting imatinib treatment a few days after the initiation of morphine therapy also reversed established tolerance to morphine, while withdrawing imatinib therapy allowed morphine tolerance to re-emerge, “indicating that imatinib only temporarily reversed the processes that cause tolerance,” the team writes. Moreover, the ability of imatinib to block tolerance appeared specific to the opiod drug, and had no effect on preventing tolerance to clonidine.

Because imatinib acts at the level of other tyrosine kinases as well as PDGFR, the researchers needed to confirm that the drug’s effects on morphine tolerance were due to its inhibition of PDGFR-β specifically. To this end, animals were treated with either morphine alone, or with morphine plus a fusion construct comprising PDGFR-β and an antibody Fc portion (PDGFR-β–Fc) that scavenges the released PDGF subunit B (PDGF-B). Animals receiving morphine plus PDGFR-β–Fc similarly exhibited tolerance reversal, which supported the notion that “tolerance inhibition is PDGFR-β selective and is due to opioid-induced release of PDGF-B,” the investigators remark.

The possibility still existed that PDGF release might act to decrease morphine analgesia or basal response latencies, which would result in only an ‘apparent’ tolerance to the drug, the team continues. To test this possibility, they treated rats using either morphine, a PDGF subunit B homodimer (PDGF-BB), both morphine and PDGF-BB, or morphine, PDGF-BB and imatinib, or morphine and imatinib. Interestingly, analgesic responses were similar for rats receiving morphine alone or morphine and PDGF-BB, which suggested that PDGF-BB didn’t interfere with morphine analgesia or itself become antianalgesic over time. Moreover, PDGF-BB completely abolished tolerance inhibition by imatinib. In addition,  rats given PDGF-BB for four days were tolerant a finding which that PDGFR-β activation could directly cause morphine tolerance, the authors note

“These findings could have profound clinical implications for the millions of people suffering from chronic intractable pain,” they conclude. “Given the widespread use of imatinib and morphine, it may seem surprising that tolerance inhibi­tion by imatinib has not been previously observed. We hypothesize that current imatinib treatments do not achieve the level of imatinib in the central nervous system needed to inhibit tolerance … On the basis of our findings, we postulate that PDGFR-β inhibition blocks tolerance using two mechanisms: a rapid effect causing most of the reversal and a slower process that completely restores analgesia.”

The overall data also indicate that NMDAR and PDGFR- β, modulate tolerance to morphine independently, they point out. PDGFR-β activation inhibits NMDARs, so if common signaling pathways mediated morphine tolerance induced by both PDGFR activation and NMDAR activation, then PDGFR-β agonists, rather than inhibitors, might block tolerance. Moreover, NMDAR antagonists alone can cause analgesia and effect sustained reversal of morphine tolerance. Conversely, PDGF-BB doesn’t alter mor­phine analgesia or baseline responses, or change the rate of morphine tolerance development. 

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