Glia, TollR4 and opioid issues, value of naltrexone 

Spinal administration of LPS produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept. LPS, a TLR4 agonist induces spinal release of PGE(2) and TNF.

Intrathecal pentoxifylline blunted PGE(2) and TNF release, while i.t. minocycline only prevented the spinal release of TNF.

Conclusion:  Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia.^[1]

Toll receptors also exist in peripheral nerve tissue, Schwann cells express relatively high levels of TLRs, with especially TLR3 and TLR4. Similar to microglia in the brain, Schwann cells might be sentinel cells in the PNS.^[2] TLR4 inhibitors are novel targets for gliopathic pain.^[3]

Morphine non-stereoselectively induces TLR4 signaling, and that can be blocked by a classical TLR4 antagonist and non-stereoselectively by opioid antagonists such as naloxone. ^[4] Naloxone and natrexone therefore are interesting compounds for the treatment of neuropathic pain. These compounds could also counteract opioid-induced spinal proinflammatory cytokines and provide a novel mechanism for analgesia in neuropathic/gliopathic pain.^[5]

But Toll 4 is not the only activating pathway. There seems to be at least 5 major paths to activate microglia: 

1. fractalkine,
2. interferon-gamma,
3. monocyte chemoattractant protein-1,
4. TLR4 ^[6], and
5. P2X4

^[7] 

October 2010, Jan M. Keppel Hesselink, MD, PhD 

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