Neuropathic pain remains a prevalent clinical problem because it is often poorly responsive to the currently used
analgesics, thus it is crucial the identification of new potential targets and drugs. Recent evidence indicated that microglial cells in the spinal cord are critically involved in the development and maintenance of
neuropathic pain, with a pivotal role of
toll-like receptor 4 (TLR4). Binding of an endogenous
ligand to TLR4 might be considered an important step in the regulation of microglia activity in
pain facilitation, suggesting that a mechanism aimed to inhibit such a binding could be effective against
neuropathic pain. We have synthesized new
ligands to TLR4 with antagonistic activity. In the present work we evaluated the efficacy of the most potent TLR4 antagonist synthesized by us (FP-1), administered in mice with
painful neuropathy. The repeated treatment of neuropathic mice with
FP-1 (5-10 mg/kg, i.p.) evoked a relief of both
thermal hyperalgesia and
mechanical allodynia, whereas the administration of the highest dose to TLR4 knockout neuropathic mice revealed that in the absence of
TLR4 receptor, the compound lost its efficacy. As consequence of TLR4 binding, the repeated treatment with
FP-1 prevented the activation of the
transcription factor NF-kB and the
TNFalpha overproduction in the spinal cord. Together, our findings support the previous evidence indicative for a contribution of glial TLR4 to the initiation of
neuropathic pain, suggest it as potential innovative target to treat this debilitating disease, and propose
FP-1 as lead compound for the development of new effective drugs.