Chemokine CCL21 in anterior cingulate cortex is involved in chronic neuropathic pain in a rat model

doi:10.3969/j.issn.2095-4344.2982

Abstract

Abstract: BACKGROUND: The pathogenesis of chronic pathological pain is yet unknown. Some studies have shown that after spinal cord injury, CCL21 can activate microglia in the central nervous system and is expressed only in damaged neurons, promoting the formation of chronic pathological pain.
OBJECTIVE: To investigate whether the anterior cingulate cortex is involved in the formation of chronic pathological pain after inferior orbital nerve ligation in rats, and whether blocking chemokine CCL21 in the anterior cingulate cortex can reduce the chronic neuropathic pain.
METHODS: A total of 80 male Sprague-Dawley rats were randomly divided into 4 groups with 20 rats in each group. In the sham group, only the infraorbital nerve of the rats was exposed; in the model group, the left infraorbital nerve was ligated; in the anti-CCL21 group, CCL21 neutralizing antibodies was administered to the anterior cingulate cortex of the rats on the 7th day after surgery; and in the PBS control group, PBS solution was given into the anterior cingulate cortex of rats on the 7th day after surgery. Rats in the sham and model groups were subjected to behavioral tests on the 3rd, 5th, 7th, and 14th days after surgery, and those in the anti-CCL21 and PBS control groups were subjected to the behavioral test at 6 hours after administration. All rats were sacrificed under anesthesia after behavioral tests. The cortical tissues were taken from the anterior cingulate, and the protein content of CCL21 was determined by western blot and immunofluorescence.
RESULTS AND CONCLUSION: The pain threshold of the rats in the model group was lower than that in the sham group, and the expression of CCL21 in the anterior cingulate cortex was significantly higher in the model group than the sham group. After the administration of CCL21 neutralizing antibody, the expression of CCL21 was reduced to some extents, and the rat pain threshold was increased accordingly. These findings reveal that the anterior cingulate cortex of rats may be involved in the production of chronic pathological pain, and the administration of CCL21 neutralizing antibody can relief the pain.

Key words: chronic pain, pathological, ligation of infraorbital nerve, anterior cingulate cortex, microglia, chemotactic factor, CCL21

CLC Number:

R459.9
R318

Zhi Yibo, Zhang Jie, Liu Jian, Li Weiyan. Chemokine CCL21 in anterior cingulate cortex is involved in chronic neuropathic pain in a rat model[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(2): 242-246.

Figures/Tables 5

References

[1] Jensen TS , Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014; 13(9):924-935.
[2] Arendt-Nielsen L , Morlion B, Perrot S, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018;22:216-241.
[3] Dahan A, van Velzen M, Niesters M. Comorbidities and the complexities of chronic pain. Anesthesiology. 2014;121:1-3.
[4] Coyle DE. Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynicbehavior. Glia. 1998;23(1): 75-83.
[5] De Jong EK, Dijkstra IM, Hensens M, et al. Vesicle-mediated transport and release of CCL21 in endangered neurons:a possible explanation for microglia activation remote from a primary lesion. J Neurosci. 2005;25(33): 7548-7557.
[6] Belsky J, Pluess M. Beyond diathesis stress: differential susceptibility to environmental influences. Psychol Bull. 2009;135(6): 885-908.
[7] Verge GM, Milligan ED, Maier SF, et al. Fractakine (CX3CL1) and fractakine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci. 2004;20(5): 1150-1160.
[8] Milligan ED, Sloane EM, Watkins LR. Glia in pathological pain: A role for fractalkine. J Neuroimmunol. 2008;198(1/2): 113-120.
[9] Peoples LL. Neuroscience: will, anterior cingulate cortex, and addiction. Science. 2002;296(5573): 1623-1624.
[10] Wei F, Guo W, Zou SP, et al. Supraspinal Glial-Neuronal interactions contribute to descending pain facilitation. J Neurosci. 2008;28(42): 10482-10495.
[11] Milligan ED, Twining C, Chacur M, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23(3): 1026-1040.
[12] Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals. 2005;14(4): 166-174.
[13] Rappert A, Biber K, Nolte C, et al. Secondary lymphoid tissue chemokine (CCL21) activates CXCR3 to trigger a Cl- current and chemotaxis in murine microglia. J Immunol. 2002;168(7):3221.
[14] Soto H, Wang W, Strieter RM, et al. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proc Natl Acad Sci U S A. 1998;95(14): 8205-8210.
[15] Love M , Sandberg JL , Ziarek JJ , et al. Solution Structure of CCL21 and Identification of a Putative CCR7 Binding Site. Biochemistry. 2012; 51(3):733-735.
[16] Tsuda M, Masuda T, Tozaki-Saitoh H, et al. P2X4 receptors and neuropathic pain. Front Cell Neurosci. 2013;7:191
[17] Jiang Y, Bai J, Tang L, et al. Anti-CCL21 antibody attenuates infarct size and improves cardiac remodeling after myocardial infarction. Cell Physiol Biochem. 2015;37(3):979-990.
[18] Biber K, Boddeke E. Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. Front Cell Neurosci. 2014;8:210.
[19] Xuan W, Qu Q, Zheng B, et al. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines. J Leukoc Biol. 2014; 97(1):61-69.
[20] Biber K , Tsuda M , Tozaki-Saitoh H , et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. Embo J. 2011;30(9):1864-1873.
[21] Honjoh K, Nakajima H, Hirai T,et al. Relationship of Inflammatory Cytokines From M1-Type Microglia/Macrophages at the Injured Site and Lumbar Enlargement With Neuropathic Pain After Spinal Cord Injury in the CCL21 Knockout ( plt ) Mouse. Fronti Cell Neurosci. 2019; 21(9):525-526.
[22] Detloff MR, Fisher LC, Mcgaughy V, et al. Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp Neurol. 2008; 212(2):337-347.
[23] Zhou X , He X , Ren Y. Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen Res. 2014; 9(20):1787-1795.
[24] Liu J, Feng X , Yu M , et al. Pentoxifylline attenuates the development of hyperalgesia in a rat model of neuropathic pain. Neurosci Lett. 2007; 412(3):268-272.