Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury–induced Nociceptive Hypersensitivity

Abstract

Background Peripheral nerve injury–induced gene alterations in the dorsal root ganglion (DRG) and spinal cord likely participate in neuropathic pain genesis. Histone methylation gates gene expression. Whether the suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, contributes to nerve injury–induced nociceptive hypersensitivity is unknown. Methods Quantitative real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, or immunohistochemistry were carried out to examine the expression of SUV39H1 mRNA and protein in rat DRG and dorsal horn and its colocalization with DRG μ-opioid receptor (MOR). The effects of a SUV39H1 inhibitor (chaetocin) or SUV39H1 siRNA on fifth lumbar spinal nerve ligation (SNL)–induced DRG MOR down-regulation and nociceptive hypersensitivity were examined. Results SUV39H1 was detected in neuronal nuclei of the DRG and dorsal horn. It was distributed predominantly in small DRG neurons, in which it coexpressed with MOR. The level of SUV39H1 protein in both injured DRG and ipsilateral fifth lumbar dorsal horn was time dependently increased after SNL. SNL also produced an increase in the amount of SUV39H1 mRNA in the injured DRG (n = 6/time point). Intrathecal chaetocin or SUV39H1 siRNA as well as DRG or intraspinal microinjection of SUV39H1 siRNA impaired SNL-induced allodynia and hyperalgesia (n = 5/group/treatment). DRG microinjection of SUV39H1 siRNA also restored SNL-induced DRG MOR down-regulation (n = 6/group). Conclusions The findings of this study suggest that SUV39H1 contributes to nerve injury–induced allodynia and hyperalgesia through gating MOR expression in the injured DRG. SUV39H1 may be a potential target for the therapeutic treatment of nerve injury–induced nociceptive hypersensitivity.

The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity

“…Consistent with previous studies (19, 22, 23), morphine analgesia on day 3 after CCI significantly declined compared to that on day 3 post-sham surgery on the ipsilateral side of the vehicle-injected group (Fig. 7A).…”

“…In line with previous studies in a spinal nerve injury–induced neuropathic pain model (19, 20), the phosphorylation of ERK1/2 (but not total ERK1/2) and GFAP was significantly increased in the ipsi-lateral L3/4 dorsal horn in mice subjected to CCI but not in those that received sham surgery and vehicle (Fig. 2, K and L).…”

DNMT3a‐triggered downregulation of K2p1.1 gene in primary sensory neurons contributes to paclitaxel‐induced neuropathic pain

“…The siRNA (1 μL/DRG, 40 μM) or viral solution (1 μL/DRG, 10 12 particles/ml) was injected into the left L3 and L4 DRGs with a glass micropipette . TurboFect in vivo transfection reagent (Thermo Scientific Inc.) was used as a delivery vehicle …”

“…23,24 TurboFect in vivo transfection reagent (Thermo Scientific Inc.) was used as a delivery vehicle. [25][26][27] Paclitaxel-induced neuropathic pain model Briefly, paclitaxel (4 mg/kg; dissolved in the vehicle) or vehicle (a mixture of ethanol and Cremophor EL(1:1)) was injected intraperitoneally (i.p.) every other day for 4 consecutive days.…”

Why mu‐opioid agonists have less analgesic efficacy in neuropathic pain?

“…Drastic decrease of MOR expression in dorsal root ganglia (DRG) neurons due to primary afferent fibres damage was reported years ago (Li, Kaneko, & Mizuno, ; Obara et al., ; Ossipov et al., 1995b; Rashid et al., ; Zhang, Bao et al., ). More recently, epigenetic alterations have been suggested to be responsible for this down‐regulation of MOR gene expression in the DRG and in the dorsal horn of the spinal cord, leading to limited morphine effectiveness (Rivat, ; Uchida, Ma, & Ueda, ; Uchida, Matsushita, Araki, Mukae, & Ueda, ; Zhang et al., ). Dysfunctional coupling of MOR to G protein in the DRG following nerve injury was also reported and related to the diminished analgesic efficacy of morphine in neuropathic pain (Obara et al., ).…”