Premium
Microglia attenuate the opioid‐induced depression of preBötzinger Complex (preBötC) inspiratory rhythm in vitro via a TLR4‐independent pathway
Author(s) -
Zwicker Jennifer D,
Zhang Yong,
Hutchinson Mark R,
Rice Kenner C,
Watkins Linda R,
Funk Gregory D
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1088.8
Subject(s) - damgo , opioid , agonist , (+) naloxone , tlr4 , medicine , microglia , anesthesia , pharmacology , chemistry , enkephalin , endocrinology , receptor , inflammation
Opioids activate neurons via opioid receptors (Rs) but also activate microglia via toll like receptors (TLR). Activation of microglial TLR4 impairs the ability of opioids to suppress pain and is hypothesized as pivotal in opioid‐mediated reward and tolerance. Here we test the contribution of microglia and TLR4 to the opioid‐induced respiratory depression. Using rhythmic medullary slices from neonatal rats we compared the duration of apneas evoked by locally injecting DAMGO (μ‐opiate R agonist; 50μM) into the preBötC before and after 40 min incubation in minocycline (inhibits microglial activation, 500 nM). Minocycline increased the duration of DAMGO‐evoked apnea 9.3±4.7‐fold from 33±7 to 295±76 s (n=3). In time‐matched controls, the second DAMGO‐evoked apnea was only 0.5±0.4‐fold greater than the first. The TLR4 antagonist LPS‐RS (90sec; 2000 ng/mL) had no effect on the frequency (f) depression evoked by DAMGO in the preBötC. Similarly, bath application of (+) naloxone (10μM; TLR4selective antagonist) had no effect on the f depression evoked by DAMGO (500nM) or fentanyl (1μM) in the bath. In contrast, (−) naloxone (500nM; TLR4 and μ‐opioid antagonist) reversed the depression. These data suggest that microglia attenuate the opioid‐induced respiratory depression via a mechanism that does not involve TLR4 activation. Supported by CIHR, WCHRI, AIHS, NIDA & NIAAA.