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. 2021 Mar 15;13(3):1075-1084.
eCollection 2021.

Mechanism of Cdk5-synaptophysin-SNARE pathway in acute and chronic inflammatory pain

Xichun Zhu  1 , Lihui Yue  1 , Chunyan Fan  1 , Yuting Liu  1 , Yong Wang  1 , Hongwei Zhao  1
Affiliations

Mechanism of Cdk5-synaptophysin-SNARE pathway in acute and chronic inflammatory pain

Xichun Zhu et al. Am J Transl Res. .

Abstract

Purpose: Currently, there is no favorable treatment plan for inflammatory pain, so exploring new analgesics is still a research hotspot in this area. Cyclin-dependent protein kinase 5 (Cdk5) is a pain-related protein kinase, but its mechanism in inflammatory pain has not been clarified. This research aimed to explore the mechanism of Cdk5-synaptophysin (Syn)-soluble N-ethylmaleimide-sensitivity factor (NSF) attachment protein receptor (SNARE) in acute and chronic inflammatory pain.

Methods: Rat models of acute and chronic inflammatory pain were induced by formalin and complete Freund's adjuvant (CFA), separately, and some rats injected with normal saline through intraplantar injection were divided into a control group. Thirty minutes before modeling, rats were given Cdk5 inhibitor (Roscovitine, Ros), SNARE scavenger (botulinum toxin A, BTTA), glutamate receptor inhibitor (MK801), and dimethyl sulfoxide (DMSO) through spinal canals, and the paw withdrawal threshold (PWT) and thermal withdrawal latency (PWL) at difference time points were compared.

Results: Compared with rats in the control group, those in the rat models of acute and chronic inflammatory pain showed lower PWT and PWL, higher Cdk5 enzyme level, tight correlation of Cdk5 with Syn, SNARE, p25 proteins, and higher levels of Cdk5, Syn and SNARE. And the above situation was dramatically reversed under intervention of Ros, BTTA and MK801.

Conclusion: Cdk5-Syn-SNARE pathway is a therapeutic target for inflammatory pain. Blocking the activation of this pathway is beneficial to exert analgesic effect.

Keywords: Cdk5; Chronic inflammatory pain; SNARE; synaptophysin.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Effects of Ros, BTTA, MK801 on pain response in acute pain models of rats. A. Effects of Ros, BTTA, MK801 on licking time in acute pain models of rats; B. Effects of Ros, BTTA, MK801 on frequency of biting in acute pain models of rats. Note: compared with the normal group, *means P < 0.05, **means P < 0.01, ***means P < 0.001; compared with DMSO, #means P < 0.05.
Figure 2
Figure 2
Changes of Cdk5 enzyme in acute pain models of rats. A, B. Effects of Ros, BTTA, MK801 on p-Cdk5 in DRG neurons of acute pain models of rats and its protein map; C, D. Effects of Ros, BTTA, MK801 on p-Cdk5 in spinal cord neurons of acute pain models of rats and its protein map; Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 3
Figure 3
Protein connection between Cdk5-Syn-SNARE in rat acute pain model. A. Close relationship between Cdk5-Syn protein in acute pain models of rats and its protein map; B. Close relationship between SYN-SNARE protein in acute pain models of rats and its protein map; C. Close relationship between Cdk5-p25 protein in acute pain models of rats and its protein map; D. Close relationship between Cdk5-p35 protein in acute pain models of rats and its protein map. Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 4
Figure 4
Cdk5, Syn and SNARE levels in acute pain models of rats. A. Cdk5 is dramatically up-regulated in acute pain models of rats; B. SYN is dramatically up-regulated in acute pain models of rats; C. SNARE is dramatically up-regulated in acute pain models of rats. Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 5
Figure 5
Effects of Ros, BTTA, MK801 on PWT, PWL in chronic pain models of rats. A. Effects of Ros, BTTA, MK801 on PWT in chronic pain models of rats; B. Effects of Ros, BTTA, MK801 on PWL in chronic pain models of rats. Note: compared with the normal group, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 6
Figure 6
Effects of Ros, BTTA, MK801 on Cdk5 enzyme in chronic pain models of rats. A, B. Effects of ROS, BTTA, MK801 on Cdk5 enzyme in DRG neurons of chronic pain models of rats and its protein map; C, D. Effects of ROS, BTTA, MK801 on Cdk5 enzyme in spinal cord neurons of chronic pain model of rats and its protein map. Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 7
Figure 7
Protein connection between Cdk5-Syn-SNARE in chronic pain models of rats. A. Close interaction relation of Cdk5-Syn protein in chronic pain models of rats and its protein map; B. Close interaction between Syn-SNARE protein in chronic pain models of rats and its protein map; C. Close interaction between Cdk5-p25 protein in chronic pain models of rats and its protein map; D. Close interaction between Cdk5-p35 protein in chronic pain models of rats and its protein map. Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
Figure 8
Figure 8
Cdk5, Syn and SNARE expression levels in chronic pain models of rats. A. The Cdk5 expression in chronic pain models of rats is obviously up-regulated; B. The Syn expression in chronic pain models of rats is obviously up-regulated; C. The SNARE expression in chronic pain models of rats is obviously up-regulated. Note: compared with the normal group, *means P < 0.05, **means P < 0.01; compared with DMSO, #means P < 0.05.
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