Inhibition of ASIC-Mediated Currents by Activation of Somatostatin 2 Receptors in Rat Dorsal Root Ganglion Neurons.

Abstract

Somatostatin (SST) and its analogues like octreotide (OCT) have analgesic effect on a variety of pain through peripheral SST receptors (SSTRs). However, the precise molecular mechanisms have not yet been fully elucidated. This research aimed to identify possible antinociceptive mechanisms, showing functional links of the SSTR2 and acid-sensing ion channels (ASICs). Herein, we reported that OCT inhibited the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. OCT concentration-dependently decreased the peak amplitude of acid-evoked inward currents, which were mediated by ASICs. OCT shifted concentration-response curve to protons downwards, with a decrease of 36.53 ± 5.28% in the maximal current response to pH4.5 in the presence of OCT. OCT inhibited ASIC-mediated currents through SSTR2, since the inhibition was blocked by Cyn 154806, a specific SSTR2 antagonist. The OCT inhibition of ASIC-mediated currents was mimicked by H-89, a membrane-permeable inhibitor of PKA, and reversed by internal treatment of an adenylyl cyclase activator forskolin or 8-Br-cAMP. OCT also decreased the number of action potentials induced by acid stimuli through SSTR2. Finally, peripheral administration of 20μM OCT, but not 2μM OCT, significantly relieved nociceptive responses to intraplantar injection of acetic acid in rats. This occurred through local activation of SSTR2 in the injected hindpaw and was reversed following co-application of Cyn 154806. Our results indicate that activation SSTR2 by OCT can inhibit the activity of ASICs via an intracellular cAMP and PKA signaling pathway in rat DRG neurons. These observations demonstrate a cross-talk between ASICs and SSTR2 in peripheral sensory neurons, which was a novel peripheral analgesic mechanism of SST and its analogues.