The molecular mechanism and physiological role of silent nociceptor activation

Nees, Timo A.; Wang, Na; Adámek, Pavel; Verkest, Clément; Schaefer, Irina; Virnich, Julie; Balkaya, Selin; Prato, Vincenzo; Morelli, Chiara; Zeitzschel, Nadja; Bégay, Valérie; Lee, Young Jae; Lewin, Gary R.; Heppenstall, Paul A.; Taberner, Francisco J.; Lechner, Stefan

doi:10.1101/2022.04.07.486730

Cited by 3 publications

(2 citation statements)

References 67 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Paw lifting and licking were defined as positive responses. The 50% withdrawal threshold (g) was determined by fitting the response rate vs. von Frey force curves with a Boltzmann sigmoid equation with constant bottom and top constraints equal to 0 and 100, respectively [32]. The integral of response frequency – von Frey force intensity (0.008 to 0.1 g) curves was calculated as area under the curve (AUC, A.U.…”

Section: Methodsmentioning

confidence: 99%

Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Damo

Agarwal

Simonetti

2022

Preprint

View full text Add to dashboard Cite

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microgliaex-vivoand nerve injury-induced structural remodeling and functional activation of microgliain vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia and the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.

show abstract

Section: Methodsmentioning

confidence: 99%

Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Damo

Agarwal

Simonetti

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Paw lifting and licking were defined as positive responses. The 50% withdrawal threshold (g) was determined by fitting the response rate vs. von Frey force curves with a Boltzmann sigmoid equation with constant bottom and top constraints equal to 0 and 100, respectively [34]. The integral of response frequency-von Frey force intensity (0.008 to 0.1 g) curves was calculated as area under the curve (AUC, A.U.…”

Section: Mechanical Sensitivitymentioning

confidence: 99%

Activation of β2-Adrenergic Receptors in Microglia Alleviates Neuropathic Hypersensitivity in Mice

Damo

Agarwal

Simonetti

2023

Cells

View full text Add to dashboard Cite

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.

show abstract

Paradox pain sensitivity using cuff pressure or algometer testing in patients with hemophilia

Ransmann,

Tomschi,

Schmidt

et al. 2024

Scandinavian Journal of Pain

View full text Add to dashboard Cite

Introduction Pain is a common comorbidity in patients with hemophilia (PwH) due to hemophilic arthropathy. This study aims to explore pain sensitivity in PwH methodologically investigating in cuff pressure testing compared to algometer testing. Methods 37 PwH and 35 healthy control subjects (Con) enrolled in this study. Joint health status was assessed. Subjective pain was evaluated using numeric rating scales. Pain sensitivity was measured with pressure algometry and cuff pressure algometry. Pressure pain thresholds of the algometer (PPTa) were measured at knee, ankle joints, and forehead. Subsequently, thresholds of cuff pressure were measured at the left and right lower legs (PPTcuff). In both, lower values represent higher pain sensitivity. Results PwH exerted a worse joint health status than Con. Pain sensitivity was higher in PwH compared to Con as PPTa of the knee and ankle joints were lower in PwH. No difference was observed in PPTa at the forehead. Contrastingly, lower pain sensitivity was detected in PwH by higher PPTcuff values compared to Con in both legs. Conclusion While PPTa of the knee and ankle joints are lower in PwH, PPTcuff are higher in PwH compared to Con. This reveals a paradox situation, highlighting that PwH experience local, joint- and hemophilic arthropathy-related pain, whereas pain sensitivity of non-affected soft tissue structures is lower. The reasons explaining the PPTcuff results remain elusive but might be explained by coping strategies counteracting chronic joint pain, resulting in lower sensitivity at non-affected structures.

show abstract

The molecular mechanism and physiological role of silent nociceptor activation

Cited by 3 publications

References 67 publications

Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Activation of β2-Adrenergic Receptors in Microglia Alleviates Neuropathic Hypersensitivity in Mice

Paradox pain sensitivity using cuff pressure or algometer testing in patients with hemophilia

Contact Info

Product

Resources

About