PT  - JOURNAL ARTICLE
AU  - Zhi Zhang
AU  - Zhizhong Z. Pan
TI  - Synaptic Mechanism for Functional Synergism between δ- and μ-Opioid Receptors
AID  - 10.1523/JNEUROSCI.5968-09.2010
DP  - 2010 Mar 31
TA  - The Journal of Neuroscience
PG  - 4735--4745
VI  - 30
IP  - 13
4099  - http://www.jneurosci.org/content/30/13/4735.short
4100  - http://www.jneurosci.org/content/30/13/4735.full
SO  - J. Neurosci.2010 Mar 31; 30
AB  - By sustained activation of μ-opioid receptors (MORs), chronic opioids cause analgesic tolerance, physical dependence, and opioid addiction, common clinical problems for which an effective treatment is still lacking. Chronic opioids recruit δ-opioid receptors (DORs) to plasma membrane through exocytotic trafficking, but the role of this new DOR and its interaction with existing MOR in brain functions and in these clinical problems remain largely unknown. In this study, we investigated the mechanisms underlying synaptic and behavioral actions of chronic morphine-induced DORs and their interaction with MORs in nucleus raphe magnus (NRM) neurons important for opioid analgesia. We found that the emerged DOR inhibited GABAergic IPSCs through both the phospholipase A2 (PLA2) and cAMP/protein kinase A (PKA) signaling pathways. MOR inhibition of IPSCs, normally mediated predominantly by the PLA2 pathway, was additionally mediated by the cAMP/PKA pathway, with MOR potency significantly increased after chronic morphine treatment. Isobologram analysis revealed a synergistic DOR–MOR interaction in their IPSC inhibition, which was dependent on upregulated activities of both the PLA2 and cAMP/PKA pathways. Furthermore, DOR and MOR agonists microinjected into the NRM in vivo also produced a PLA2-dependent synergism in their antinociceptive effects. These findings suggest that the cAMP/PKA pathway, upregulated by chronic opioids, becomes more important in the mechanisms of both MOR and DOR inhibition of GABA synaptic transmission after chronic opioid exposure, and DORs and MORs are synergic both synaptically and behaviorally in producing analgesic effects in a PLA2-dependent fashion, supporting the potential therapeutic use of DOR agonists in pain management under chronic opioid conditions.