title: (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychology & Neuroscience, University of Colorado at Boulder, 80309-0345, USA. susannah.lewis@colorado.edu
authors.forename: Susannah S
authors.initials: SS
authors.lastname: Lewis
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Yingning
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007279:Injections, Subcutaneous; D055666:Lipopeptides / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009270:Naloxone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000150:complications; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D055666:Lipopeptides; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; C508075:Pam(3)CSK(4) peptide; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D009270:Naloxone; D000469:Alkaline Phosphatase