The possible influence of minocycline on analgesia after opioid receptors ligands.

<p>In our opinion, activated spinal microglia are key factors in the development of neuropathic pain and play a major role in the antagonizing of some opioids effectiveness. The results of our paper show for the first time that that DOR, in contrast to MOR and KOR, is not present in microglial cells. This phenomenon might be responsible for the different analgesic effects of MOR, KOR and DOR ligands (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104420#pone-0104420-g002" target="_blank">Fig. 2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104420#pone-0104420-g003" target="_blank">3</a>). We provide evidence that minocycline (a potent inhibitor of microglial activation and proliferation) enhances the effects of selective MOR (DAMGO; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104420#pone-0104420-g002" target="_blank">Fig. 2C,D</a>) and selective KOR (U50,488H; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104420#pone-0104420-g002" target="_blank">Fig. 2E,F</a>) agonists by inhibition of microglial cell activation. The effectiveness of DOR agonists (DPDPE, deltorphin II and SNC80) is not changed by minocycline (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104420#pone-0104420-g003" target="_blank">Fig. 3A–F</a>). Our results indicate that an important element of the effectiveness of opioid drugs in neuropathic pain is the activation of microglia. The lack of DOR receptors in these cells causes that DOR receptor-mediated analgesia is not weaker under neuropathic pain, in which there is a strong activation of microglia. Earlier inhibition of microglial activation by minocycline administration therefore did not influence the effect of DOR selective agonists. The above results indicate not only that minocycline potentiates analgesia after MOR and KOR agonists but also that DOR is a potentially important target in the search for new drugs that would be effective against neuropathic pain.