RT Journal Article
SR Electronic
T1 Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 10769
OP 10781
DO 10.1523/JNEUROSCI.3480-15.2016
VO 36
IS 42
A1 Jami L. Saloman
A1 Nicole N. Scheff
A1 Lindsey M. Snyder
A1 Sarah E. Ross
A1 Brian M. Davis
A1 Michael S. Gold
YR 2016
UL http://www.jneurosci.org/content/36/42/10769.abstract
AB Designer receptors exclusively activated by designer drugs (DREADDs) are an advanced experimental tool that could potentially provide a novel approach to pain management. In particular, expression of an inhibitory (Gi-coupled) DREADD in nociceptors might enable ligand-dependent analgesia. To test this possibility, TRPV1-cre mice were used to restrict expression of Gi-DREADDs to predominantly C-fibers. Whereas baseline heat thresholds in both male and female mice expressing Gi-DREADD were normal, 1 mg/kg clozapine-N-oxide (CNO) produced a significant 3 h increase in heat threshold that returned to baseline by 5 h after injection. Consistent with these behavioral results, CNO decreased action potential firing in isolated sensory neurons from Gi-DREADD mice. Unexpectedly, however, the expression of Gi-DREADD in sensory neurons caused significant changes in voltage-gated Ca2+ and Na+ currents in the absence of CNO, as well as an increase in Na+ channel (NaV1.7) expression. Furthermore, CNO-independent excitatory and inhibitory second-messenger signaling was also altered in these mice, which was associated with a decrease in the analgesic effect of endogenous inhibitory G-protein-coupled receptor activation. These results highlight the potential of this exciting technology, but also its limitations, and that it is essential to identify the underlying mechanisms for any observed behavioral phenotypes.SIGNIFICANCE STATEMENT DREADD technology is a powerful tool enabling manipulation of activity and/or transmitter release from targeted cell populations. The purpose of this study was to determine whether inhibitory DREADDs in nociceptive afferents could be used to produce analgesia, and if so, how. DREADD activation produced a ligand-dependent analgesia to heat in vivo and a decrease in neuronal firing at the single-cell level. However, we observed that expression of Gi-DREADD also causes ligand-independent changes in ion channel activity and second-messenger signaling. These findings highlight both the potential and the limitations of this exciting technology as well as the necessity to identify the mechanisms underlying any observed phenotype.