Pharmacogenetic inhibition of TrkB signaling in adult mice attenuates mechanical hypersensitivity and improves locomotor function after spinal cord injury

Abstract

Brain-derived neurotrophic factor (BDNF) signals through tropomyosin receptor kinase B (TrkB), to exert various types of plasticity. The exact involvement of BDNF and TrkB in neuropathic pain states after spinal cord injury (SCI) remains unresolved. This study utilized transgenic TrkBF616 mice to examine the effect of pharmacogenetic inhibition of TrkB signaling, induced by treatment with 1NM-PP1 (1NMP) in drinking water for 5 days, on formalin-induced inflammatory pain, pain hypersensitivity, and locomotor dysfunction after thoracic spinal contusion. We also examined TrkB, ERK1/2, and pERK1/2 expression in the lumbar spinal cord and trunk skin. The results showed that formalin-induced pain responses were robustly attenuated in 1NMP-treated mice. Weekly assessment of tactile sensitivity with the von Frey test showed that treatment with 1NMP immediately after SCI blocked the development of mechanical hypersensitivity up to 4 weeks post-SCI. Contrastingly, when treatment started 2 weeks after SCI, 1NMP reversibly and partially attenuated hind-paw hypersensitivity. Locomotor scores were significantly improved in the early-treated 1NMP mice compared to late-treated or vehicle-treated SCI mice. 1NMP treatment attenuated SCI-induced increases in TrkB and pERK1/2 levels in the lumbar cord but failed to exert similar effects in the trunk skin. These results suggest that early onset TrkB signaling after SCI contributes to maladaptive plasticity that leads to spinal pain hypersensitivity and impaired locomotor function.

C-low threshold mechanoreceptor activation becomes sufficient to trigger affective pain in spinal cord-injured mice in association with increased respiratory rates

“…(A) Schematic depicting the two-chamber (light-dark) CPA apparatus, illustrating mouse positioning during stimulation ( left, optical stimulation shown ) and free exploration in the light chamber ( middle ) or transitioning between chambers ( right ). Adapted from Martin et al ( 2022 ). (B) SCI mice administered mechanical brush stimulation while confined to the dark chamber later developed a preference for the light “escape” chamber that peaked 4 weeks after injury (* p < 0.05 vs. 1 dpo).…”

“…Under sterile conditions, a skin incision and dorsal laminectomy exposed the underlying spinal cord at lower thoracic level 10 (T10). For midline contusion injuries, mice received a 70 kdyne, zero dwell time, impact onto the dorsal surface of the spinal cord with an Infinite Horizon impactor (IH-0400 Impactor, Precision Systems and Instrumentation, Fairfax Station, VA, USA) as we previously described (Parvin et al, 2021 ; Martin et al, 2022 ). Care was taken to ensure that dorsal roots were not damaged by the laminectomy or impact, and on-target bilateral bruising of the dorsal spinal cord was verified by examination under a dissecting microscope.…”

“…To provide a validated assessment of at-level, C-LTMR-mediated pain after SCI, our laboratory developed a modified CPA paradigm to model affective pain in mice using protocols adapted from previous studies (Hummel et al, 2008 ; Yang et al, 2014 ; Bagdas et al, 2016 ; Refsgaard et al, 2016 ; Wu et al, 2017 ) including our own (Martin et al, 2022 ). The custom-built CPA apparatus consisted of black and white chambers separated by a small partition.…”

C-low threshold mechanoreceptor activation becomes sufficient to trigger affective pain in spinal cord-injured mice in association with increased respiratory rates

“…Under sterile conditions, a skin incision and dorsal laminectomy exposed the underlying spinal cord at lower thoracic level 10 (T10). For midline contusion injuries, mice received a 70 kdyne, zero dwell time, impact onto the dorsal surface of the spinal cord with an Infinite Horizon impactor (IH-0400 Impactor, Precision Systems and Instrumentation, Fairfax Station, VA, USA) as we previously described (Parvin et al, 2021; Martin et al, 2022). Care was taken to ensure that dorsal roots were not damaged by the laminectomy or impact, and on-target bilateral bruising of the dorsal spinal cord was verified by examination under a dissecting microscope.…”

“…To provide a validated assessment of at-level, C-LTMR-mediated pain after SCI, our laboratory developed a modified CPA paradigm to model affective pain in mice using protocols adapted from previous studies (Hummel et al, 2008; Yang et al, 2014; Bagdas et al, 2016; Refsgaard et al, 2016; Wu et al, 2017) including our own (Martin et al, 2022). The custom-built CPA apparatus consisted of black and white chambers separated by a small partition.…”