Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Abstract

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBrain Behav Immun. Author manuscript; available in PMC 2011 January 1. preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

“…Although it was long assumed that morphine-induced microglial activation must be mediated via activation of classic opioid receptors, recent data from Hutchinson et al [10,22] contested this assumption. Their studies have suggested that such proinflammatory effects of morphine are not via classic opioid receptors, while via TLR4 signaling.…”

“…TLR4 are key initiators of innate and adaptive immune responses through production of proinflammatory cytokines and up-regulation of costimulatory molecules [7]. Though some studies indicate that TLR4 is not involved in morphine tolerance and microglial activation [8,9], many evidences have proved that morphine creates neuroinflammation not via μ-opioid receptors, but through activation of TLR4 signaling [10][11][12]. Thus, morphine-induced proinflammatory glial activation via TLR4 could potentially provide an explanation for tolerance to the analgesic effects of morphine.…”

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…As activated NF-κB mediates the expression of diverse inflammatory and immune-response mediators, the attenuation of morphine tolerance and morphine withdrawal-induced hyperalgesia after PDTC and SN50 administration may be associated with the inactivation of NF-κB and inhibition of the synthesis of its downstream pro-inflammatory cytokines (IL-1β, TNF-α, and other factors). Recent studies have revealed that TLR4 partially mediates the analgesic effects of acute and chronic morphine in the spinal cord [31] . Intrathecal administration of TLR4-targeted siRNA inhibits the production of IL-1β and TNF-α in the spinal cord and alleviates cancer pain in rats [46] .…”

“…A recent study revealed that TLR4 partially mediates the analgesic effect of morphine [31] , but whether it mediates the chronic morphine-induced NF-κB activation in the spinal cord remained unclear. Here, we found that i.t.…”

Pharmacology of Opioids and their Effects on Gastrointestinal Function

“…For example, a hetero-oligomer formed from the μ -opioid receptor and the δ -opioid receptor has increased affi nity for endomorphin-1 and leu-enkephalin. In addition to their interactions with opioid receptors, recent evidence suggests that opioids also interact with the innate immune pattern recognition receptor, Toll-like receptor 4, and that this action may impair the analgesic action of opioids but also modify drug tolerance and dependence ( 21 ). Th e complex hetero-oligomeric composition of opioid receptors off ers novel opportunities to separate the wanted eff ects of opioids (analgesia) from some of their unwanted eff ects, such as tolerance, constipation, and addiction.…”