scholarly journals Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release

2021 ◽  
Vol 22 (16) ◽  
pp. 8826
Author(s):  
Wanzhi Wang ◽  
Miaomiao Kong ◽  
Yu Dou ◽  
Shanghai Xue ◽  
Yang Liu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Safety Concern ◽  
Unmet Need ◽  
Nociceptive Neurons ◽  
Neuropeptide Release ◽  
Selective Expression ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

scholarly journals Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

2020 ◽  
Vol 132 (4) ◽  
pp. 867-880 ◽  
Author(s):  
Doaa M. Mohamed ◽  
Mohammed Shaqura ◽  
Xiongjuan Li ◽  
Mehdi Shakibaei ◽  
Antje Beyer ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mineralocorticoid Receptor ◽  
Mineralocorticoid Receptors ◽  
Mineralocorticoid Receptor Antagonist ◽  
Aldosterone Synthase ◽  
Nociceptive Neurons ◽  
Processing Enzyme ◽  
Peripheral Sensory Neurons ◽  
Synthase Inhibitor ◽  
Peripheral Sensory

Abstract Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Brain-derived neurotrophic factor derived from peripheral sensory neurons plays a critical role in pain chronification

2017 ◽  
Author(s):  
Shafaq Sikandar ◽  
Michael S. Minett ◽  
Joanne Lau ◽  
Queensta Millet ◽  
Sonia Santana-Varela ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Knockout Mice ◽  
Normal Development ◽  
Critical Role ◽  
Primary Afferent ◽  
Mechanical Hypersensitivity ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

AbstractMultiple studies support the pro-nociceptive role of brain-derived neurotrophin factor (BDNF) in pain processes in the peripheral and central nervous system. We have previously shown that nociceptor-derived BDNF is implicated in inflammatory pain. Microglial-derived BDNF has also been shown to be involved in neuropathic pain. However, the distinct contribution of primary afferent-derived BNDF to chronic pain processing remains undetermined. In this study, we used Advillin-CreERT2 mice to delete Bdnf from all adult peripheral sensory neurons. Conditional BDNF knockouts were healthy with no sensory neuron loss. Behavioural assays and in vivo electrophysiology indicated that spinal excitability was normal. Following formalin inflammation or neuropathy with a modified Chung model, we observed normal development of acute pain behaviour, but a deficit in second phase formalin-induced nocifensive responses and a reversal of neuropathy-induced mechanical hypersensitivity during the later chronic pain phase in conditional BDNF knockout mice. In contrast, we observed normal development of acute and chronic neuropathic pain in the Seltzer model, indicating differences in the contribution of BDNF to distinct models of neuropathy. We further used a model of hyperalgesic priming to examine the contribution of primary afferent-derived BDNF in the transition from acute to chronic pain, and found that primed BDNF knockout mice do not develop prolonged mechanical hypersensitivity. Our data suggest that BDNF derived from sensory neurons plays a critical role in mediating the transition from acute to chronic pain.

Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

Neuroscience ◽  
2010 ◽  
Vol 169 (1) ◽  
pp. 449-454 ◽  
Author(s):  
C. König ◽  
O. Gavrilova-Ruch ◽  
G. Segond von Banchet ◽  
R. Bauer ◽  
M. Grün ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Sensory Neurons ◽  
Receptor Desensitization ◽  
Peripheral Sensory Neurons ◽  
Μ Opioid Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Peripheral Sensory

scholarly journals A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons

Pain ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 2364-2372 ◽  
Author(s):  
Kalina Szteyn ◽  
Matthew P. Rowan ◽  
Ruben Gomez ◽  
Junhui Du ◽  
Susan M. Carlton ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Sensory Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate ◽  
Peripheral Sensory Neurons ◽  
Anchoring Protein ◽  
Peripheral Sensory

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia

2008 ◽  
Vol 294 (5) ◽  
pp. G1288-G1298 ◽  
Author(s):  
Walter E. B. Sipe ◽  
Stuart M. Brierley ◽  
Christopher M. Martin ◽  
Benjamin D. Phillis ◽  
Francisco Bautista Cruz ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Action Potentials ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Hyperalgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Afferent Neurons ◽  
Nociceptive Neurons ◽  
Afferent Fibers ◽  
Transient Receptor

Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4+/+ mice, intraluminal PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6–24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4−/− mice. PAR2-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4+/+ mice, but not from TRPV4−/− mice. The TRPV4 agonists 5′,6′-epoxyeicosatrienoic acid and 4α-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR2-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR2 increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

scholarly journals Selective conversion of fibroblasts into peripheral sensory neurons

2014 ◽  
Vol 18 (1) ◽  
pp. 25-35 ◽  
Author(s):  
Joel W Blanchard ◽  
Kevin T Eade ◽  
Attila Szűcs ◽  
Valentina Lo Sardo ◽  
Rachel K Tsunemoto ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Selective Conversion ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory
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