Chemogenetic technique to produce analgesia in mice also disrupts endogenous signaling
The designer receptors exclusively activated by designer drugs (DREADD) system can be used to suppress nociceptors
But thanks to a set of careful control experiments, researchers led by Brian Davis and Michael Gold, University of Pittsburgh, US, also find an important caveat: DREADD expression alters endogenous channel activity and signaling pathways in sensory neurons independent of the ligand used to activate the receptor.
Though these findings were not unforeseen, it’s the first time research has demonstrated such unintended consequences of DREADD technology, and it illustrates the care that pain researchers and, indeed, any researcher using this technology, must take when interpreting results from experiments using DREADDs.
“It’s not at all surprising that expression of the inhibitory DREADD [used in the study] produced a modest off-target effect.
Anytime you do anything to a cell, there are unintended changes that take place.
I think the important lesson here is to always perform appropriate control experiments,”
said Bryan Roth, University of North Carolina at Chapel Hill, US, who invented the DREADD technology but was not involved in the new study.
However, control experiments revealed a problematic and, the researchers believe, underappreciated phenomenon
this indicates that expression of the Gi-DREADD alone altered some normal channel properties of the sensory neurons.
Specifically, the researchers found a smaller action potential overshoot and longer action potential duration in neurons from V1Gi-DREADD mice compared to those from controls.
“The DREADDs worked just like we thought they would to produce analgesia. Unfortunately, Gi-DREADD expression also had unintended consequences,” Gold told PRF.
Not so unexpected?
“Gi-DREADD expression really produced a lot of changes in these neurons. In retrospect, that shouldn’t have been so surprising, given that proteins in a membrane intricately communicate with a variety of signaling molecules,” said Gold. “If you insert a whole bunch of G protein in the membrane, it’s going to start influencing how all the membrane proteins talk to each other,” he explained.
Roth noted that while the current study is the first report of unintended effects of DREADD expression, the field of optogenetics has seen several reports of similar unintended effects, such as those resulting from heat generated by optical stimulation (Stujenske et al., 2015; Otchy et al., 2015).
However, given the relatively small increase in nociceptive threshold observed in response to CNO, Gold predicts that, although a lower level of expression may reduce the level of compensatory changes, it would also be unlikely to produce enough DREADD to create the intended effect.
I worry that any “new” kinds of pain medications could have dreadful side effects that only appear later, like Immunotherapy for Cancer Attacks Organs.