Elsevier

The Journal of Pain

Volume 13, Issue 5, May 2012, Pages 498-506
The Journal of Pain

Original Report
(+)-Naloxone, an Opioid-Inactive Toll-Like Receptor 4 Signaling Inhibitor, Reverses Multiple Models of Chronic Neuropathic Pain in Rats

https://doi.org/10.1016/j.jpain.2012.02.005Get rights and content
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Abstract

Previous work demonstrated that both the opioid antagonist (-)-naloxone and the non-opioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2–4 months) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+)-naloxone has comparable pharmacokinetics to (-)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that toll-like receptor 2 (TLR2) has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+)-naloxone as a novel candidate for the treatment of neuropathic pain.

Perspective

These studies demonstrated that (+)-naloxone, a systemically available, blood-brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+)-naloxone, or similar compounds, be considered as a candidate novel, first-in-class treatment for neuropathic pain.

Key words

TLR4
neuropathic pain
chronic constriction injury
spinal nerve ligation
HEK293-TLR4

Cited by (0)

This work was funded in part by NIH Grants DA024044, DE017782, DA023132 and NIDA contract N01DA-9-8883. This work was also supported in part by the NIH Intramural Research Programs of NIDA and NIAAA. Mark R. Hutchinson is a NHMRC CJ Martin Fellow (ID 465423; 2007-2010) and an Australian Research Council Research Fellow (DP110100297). HEK-TLR4 cells were gifted from Avigen.