(+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats.

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Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR

(+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats.

J Pain. 2012 May;13(5):498-506. doi: 10.1016/j.jpain.2012.02.005. Epub 2012 Apr 20.

PubMed ID

22520687 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Naloxone	Toll-like receptor 4	Protein	Humans	Unknown	Inhibitor	Details