Specific targeting of microglia using hydroxyl group terminated dendrimer(G4) conjugated with anti-inflammatory drug mitigates neuropathic pain

Background: Accumulating evidence on the causal role of spinal cord microglia activation in the development of neuropathic pain after peripheral nerve injury (PNI) suggests that microglial activation inhibitors might be useful... [ view full abstract ]

Background: Accumulating evidence on the causal role of spinal cord microglia activation in the development of neuropathic pain after peripheral nerve injury (PNI) suggests that microglial activation inhibitors might be useful analgesics for neuropathic pain. Studies also have shown that polyamidoamine (PAMAM) dendrimer may function as a drug delivery vehicle to microglia in the central nervous system. In this regard, we developed PAMAM dendrimer-conjugated triamcinolone acetonide (D-TA), a previously identified microglial activation inhibitor, and tested its analgesic efficacy in a mouse PNI model.

Result: PAMAM dendrimer was delivered selectively to spinal cord microglia upon intrathecal (i.t.) administration. D-TA inhibited LTA-induced proinflammatory gene expression in primary glial cells. In addition, D-TA administration (i.t.) inhibited PNI-induced spinal cord microglial activation and the expression of pain-related genes in the spinal cord, including Nox2, IL-1β, TNF-α, and IL-6. D-TA administration right after nerve injury almost completely reversed PNI-induced mechanical allodynia for up to 3 days. Meanwhile, D-TA administration 1.5 days post injury (dpi) significantly attenuated mechanical allodynia.

Conclusion: Our data demonstrate that D-TA inhibits spinal cord microglia activation and attenuates neuropathic pain after PNI, which has therapeutic implications for the treatment of neuropathic pain