Gonadal hormone–dependent nociceptor sensitization maintains nociplastic pain state in female mice

Hankerd, Kali; Koo, Hyeon‐Kyoung; McDonough, Kathleen E; Wang, Jigong; Pariyar, Ramesh; Tang, Shao-Jun; Chung, Jin Mo; La, Jun–Ho

doi:10.1097/j.pain.0000000000002715

Cited by 4 publications

(1 citation statement)

References 45 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are significant sex differences in the generation of pain, however, previous mouse and rat studies have predominately used males only [76]. Gonadectomized and gonadal hormone replacement alter the response of BDNF and the activity-induced pain model [67, 77]. Interestingly, ovariectomy recapitulated the effects of BDNF in female mice normally observed in male mice, showing increased expression of glutamate receptor GluN2B, decreased expression of the neuron specific chloride extruder KCC2, and potentiated NMDAR excitatory postsynaptic potentials [70], suggesting that hormones may modulate the effects of BDNF.…”

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Hayashi,

Lesnak,

Plumb

et al. 2023

Preprint

View full text Add to dashboard Cite

Activity-induced muscle pain increases release of interleukin-1β (IL-1β) in muscle macrophages and the development of pain is prevented by blockade of IL-1β. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1β, which subsequently activate sensory neurons to secrete BDNF. To test this hypothesis, we used an animal model of activity-induced pain induced by repeated intramuscular acidic saline injections combined with fatiguing muscle contractions. Intrathecal or intramuscular injection of inhibitors of BDNF-Tropomyosin receptor kinase B (TrkB) signaling, ANA-12 or TrkB-Fc, reduced the decrease in muscle withdrawal thresholds in male, but not in female, mice when given before or 24hr after, but not 1 week after induction of the model. BDNF messenger ribonucleic acid (mRNA) was significantly increased in L4–L6 dorsal root ganglion (DRG), but not the spinal dorsal horn or gastrocnemius muscle, 24hr after induction of the model in either male or female mice. No changes in TrkB mRNA or p75 neurotrophin receptor mRNA were observed. BDNF protein expression via immunohistochemistry was significantly increased in L4–L6 spinal dorsal horn and retrogradely labelled muscle afferent DRG neurons, at 24hr after induction of the model in both sexes. In cultured DRG, fatigue metabolites combined with IL-1β significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1β, BDNF from primary DRG neurons and contribute to activity-induced muscle pain only in males, while there were no sex differences in the changes in expression observed in BDNF.

show abstract

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Hayashi,

Lesnak,

Plumb

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Temporal and spatial summation of laser heat stimuli in cultured nociceptive neurons of the rat

Jubileum

Binzen

Treede

et al. 2022

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

We studied the efficacy of a near-infrared laser (1475 nm) to activate rat dorsal root ganglion (DRG) neurons with short punctate radiant heat pulses (55 µm diameter) and investigated temporal and spatial summation properties for the transduction process for noxious heat at a subcellular level. Strength-duration curves (10–80 ms range) indicated a minimum power of 30.2mW for the induction of laser-induced calcium transients and a chronaxia of 13.9 ms. However, threshold energy increased with increasing stimulus duration suggesting substantial radial cooling of the laser spot. Increasing stimulus duration demonstrated suprathreshold intensity coding of calcium transients with less than linear gains (Stevens exponents 0.29/35mW, 0.38/60mW, 0.46/70mW). The competitive TRPV1 antagonist capsazepine blocked responses to short near-threshold stimuli and significantly reduced responses to longer duration suprathreshold heat. Heating 1/3 of the soma of a neuron was sufficient to induce calcium transients significantly above baseline (p < 0.05), but maximum amplitude was only achieved by centering the laser over the entire neuron. Heat-induced calcium increase was highest in heated cell parts but rapidly reached unstimulated areas reminiscent of spreading depolarization and opening of voltage-gated calcium channels. Full intracellular equilibrium took about 3 s, consistent with a diffusion process. In summary, we investigated transduction mechanisms for noxious laser heat pulses in native sensory neurons at milliseconds temporal and subcellular spatial resolution and characterized strength duration properties, intensity coding, and spatial summation within single neurons. Thermal excitation of parts of a nociceptor spread via both membrane depolarization and intracellular calcium diffusion.

show abstract

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Hayashi,

Lesnak,

Plumb

et al. 2024

Brain, Behavior, and Immunity

View full text Add to dashboard Cite

Gonadal hormone–dependent nociceptor sensitization maintains nociplastic pain state in female mice

Abstract: Supplemental Digital Content is Available in the Text.The development of persistent nociceptor activity at the previously injured area, which maintains a nociplastic pain state in females, depends on female gonadal hormones.

Cited by 4 publications

References 45 publications

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Temporal and spatial summation of laser heat stimuli in cultured nociceptive neurons of the rat

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice

Contact Info

Product

Resources

About