Figure 8.

Proposed mechanism of CLON-DELT analgesic synergy localized to primary afferent terminals in the dorsal horn of the spinal cord. A, Model of DOP agonist-induced DOP insertion coinciding with neuropeptide release (adapted from Bao et al., 2003). Activation of DOPs through administration of DELT causes activation of PLC (presumably through G_q), thereby increasing intracellular Ca²⁺ concentrations via IP₃ receptors. This spike in Ca²⁺ mediates exocytosis of LDCVs, thus releasing neuropeptides and inserting intracellular “reserve” DOPs to the plasma membrane. B, Proposed model of CLON-DELT synergy mediated by PKC through coactivation of α₂ARs and DOPs. Coactivation of α₂ARs and DOPs causes neuropeptide release at a 100-fold lower concentration than DELT administration alone via the same mechanism as A. In contrast to DOP agonist-induced DOP insertion, however, coactivation of α₂ARs and DOPs causes activation of PKC through increased levels of DAG. Activation of PKC, in turn, mediates the synergistic interaction of α₂ARs and DOPs. One of several hypotheses for this mechanism is that the phosphorylation target(s) of PKC allow enhanced G_i/o coupling of both the α_2AAR and DOP (yellow stars). An alternative hypothesis is that activation of PKC favors the formation of α₂AR/DOP heterodimers with an enhanced inhibitory mode of action.