The temporal expression of circulating microRNAs after acute experimental pain in humans

Giordano, Rocco; Gerra, Maria Carla; Okutani, Hiroai; Vecchio, Silvia Lo; Stensballe, Allan; Petersen, Kristian Kjær; Arendt‐Nielsen, Lars

doi:10.1002/ejp.2062

Cited by 2 publications

(3 citation statements)

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“…25 Increased let-7b levels were found in human cerebrospinal fluid (CSF) and blood under disease and pain conditions. 17,31 Intriguingly, let-7b has the capability to bind to toll-like receptor-7 (TLR7). 15,44 Traditionally activated by single-strand RNAs, TLR7 activation leads to the expression of inflammatory genes and innate immune responses Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.…”

Section: Introductionmentioning

confidence: 99%

“…8 A rapid increase in circulating micro-RNAs was detected within 0.5 to 24 hours in human experimental pain. 17 In addition, distinct circulating miRNA signatures have been identified in rodent models of pain. 48 miRNA lethal-7 (let-7), first discovered in the nematode, 49 stands out as one of the most abundant and evolutionarily conserved miRNAs across species.…”

Section: Introductionmentioning

confidence: 99%

“…8 A rapid increase in circulating microRNAs was detected within 0.5 to 24 hours in human experimental pain. 17 In addition, distinct circulating miRNA signatures have been identified in rodent models of pain. 48…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA let-7b enhances spinal cord nociceptive synaptic transmission and induces acute and persistent pain through neuronal and microglial signaling

Chen,

Jiang,

Berta

et al. 2024

Pain

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Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 μg) induced short-term (<24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7 −/− or Trpa1 −/− mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 μg), induced persistent mechanical allodynia for >2 weeks, which was abolished in Tlr7 −/− mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b–induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator.

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