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

JOURNAL OF PAIN

卷:13

Article

Lewis, Susannah S.¹  Loram, Lisa C.¹  Hutchinson, Mark R.²  Li, Chien-Ming³  Zhang, Yingning¹  Maier, Steven F.¹  Huang, Yong³  Rice, Kenner C.^4,5  Watkins, Linda R.¹ 

[1] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA

[2] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA, Australia

[3] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Drug Studies Unit, San Francisco, CA 94143 USA

[4] NIDA, Chem Biol Res Branch, Rockville, MD USA

[5] NIAAA, NIH, Rockville, MD 20852 USA

关键词: TLR4;    neuropathic pain;    chronic constriction injury;    spinal nerve ligation;    HEK293-TLR4;   

DOI  :  10.1016/j.jpain.2012.02.005

来源: Elsevier

【 摘 要 】

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. (C) 2012 by the American Pain Society. Published by Elsevier Inc. All rights reserved

【 授权许可】

Free