Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Target Concepts:
Gene/Protein
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Query: UMLS:C0344307 (
analgesia
)
28,200
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the
collapsin response mediator protein 2
(
CRMP-2
), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT-CBD3
analgesia
has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects. We hypothesized that these issues could be addressed by expressing CBD3 encoded by high-expression vectors in primary sensory neurons. We constructed an adeno-associated viral (AAV) vector expressing recombinant fluorescent CBD3 peptide and injected it into lumbar dorsal root ganglia (DRGs) of rats before spared nerve injury (SNI). We show that selective expression of enhanced green fluorescent protein (EGFP)-CBD3 in lumbar 4 (L4) and L5 DRG neurons and their axonal projections results in effective attenuation of nerve injury-induced neuropathic pain in the SNI model. We conclude that AAV-encoded CBD3 delivered to peripheral sensory neurons through DRG injection may be a valuable approach for exploring the role of presynaptic VGCCs and long-term modulation of neurotransmission, and may also be considered for development as a gene therapy strategy to treat chronic neuropathic pain.
...
PMID:Sustained relief of neuropathic pain by AAV-targeted expression of CBD3 peptide in rat dorsal root ganglion. 2415 82
The peripherally expressed voltage-gated sodium Na
V
1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na
V
1.7 has been the focus of intense investigation but, to date, no Na
V
1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na
V
1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na
V
1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na
V
1.7 therapeutics is currently unknown. The demonstration that loss of Na
V
1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only Na
V
1.7 may be insufficient for
analgesia
. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial. Thus, additional new targets - regulators, modulators - are needed. In this context, we mine the literature for the known interactome of Na
V
1.7 with a focus on protein interactors that affect the channel's trafficking or link it to opioid signaling. As a case study, we present antinociceptive evidence of allosteric regulation of Na
V
1.7 by the cytosolic
collapsin response mediator protein 2
(
CRMP2
). Throughout discussions of these possible new targets, we offer thoughts on the therapeutic implications of modulating Na
V
1.7 function in chronic pain.
...
PMID:Mining the Na
v
1.7 interactome: Opportunities for chronic pain therapeutics. 3069 28
