Dataset Information

Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons.

ABSTRACT: 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.

SUBMITTER: Saloman JL

PROVIDER: S-EPMC5083007 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons.

Saloman Jami L JL Scheff Nicole N NN Snyder Lindsey M LM Ross Sarah E SE Davis Brian M BM Gold Michael S MS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20161001 42

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, ...[more]

PMID: 27798132

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Project description:BackgroundWe investigated whether transcranial magnetic stimulation (rTMS) over the primary somatosensory cortex (S1) and sensory stimulation (SS) could promote upper limb recovery in participants with subacute stroke.MethodsParticipants were randomized into four groups: rTMS/Sham SS, Sham rTMS/SS, rTMS/SS, and control group (Sham rTMS/Sham SS). Participants underwent ten sessions of sham or active rTMS over S1 (10 Hz, 1,500 pulses, 120% of resting motor threshold, 20 min), followed by sham or active SS. The SS involved active sensory training (exploring features of objects and graphesthesia, proprioception exercises), mirror therapy, and Transcutaneous electrical nerve stimulation (TENS) in the region of the median nerve in the wrist (stimulation intensity as the minimum intensity at which the participants reported paresthesia; five electrical pulses of 1 ms duration each at 10 Hz were delivered every second over 45 min). Sham stimulations occurred as follows: Sham rTMS, coil was held while disconnected from the stimulator, and rTMS noise was presented with computer loudspeakers with recorded sound from a real stimulation. The Sham SS received therapy in the unaffected upper limb, did not use the mirror and received TENS stimulation for only 60 seconds. The primary outcome was the Body Structure/Function: Fugl-Meyer Assessment (FMA) and Nottingham Sensory Assessment (NSA); the secondary outcome was the Activity/Participation domains, assessed with Box and Block Test, Motor Activity Log scale, Jebsen-Taylor Test, and Functional Independence Measure.ResultsForty participants with stroke ischemic (n = 38) and hemorrhagic (n = 2), men (n = 19) and women (n = 21), in the subacute stage (10.6 ± 6 weeks) had a mean age of 62.2 ± 9.6 years, were equally divided into four groups (10 participants in each group). Significant somatosensory improvements were found in participants receiving active rTMS and active SS, compared with those in the control group (sham rTMS with sham SS). Motor function improved only in participants who received active rTMS, with greater effects when active rTMS was combined with active SS.ConclusionThe combined use of SS with rTMS over S1 represents a more effective therapy for increasing sensory and motor recovery, as well as functional independence, in participants with subacute stroke.Clinical trial registration[clinicaltrials.gov], identifier [NCT03329807].

Dataset Information

Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons.

Significance statement

Publications

Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons.

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