The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain

Guo,Chi-Hua; Bai,Lu; Wu,Huang-Hui; Yang,Jing; Cai,Guo‑Hong; Wang,Xin; Wu,Sheng-Xi; Ma,Wei

doi:10.3892/ijmm.2016.2763

The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain

Authors:
- Chi-Hua Guo
- Lu Bai
- Huang-Hui Wu
- Jing Yang
- Guo‑Hong Cai
- Xin Wang
- Sheng-Xi Wu
- Wei Ma
View Affiliations

Affiliations: Department of Orthopedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Medical Imaging, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Anesthesiology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou, Fujian 350025, P.R. China, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310027, P.R. China, Department of Neurobiology and Collaborative Innovation Center for Brain Science, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: September 30, 2016 https://doi.org/10.3892/ijmm.2016.2763
Pages: 1433-1442
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal ‘neuron-astrocytic’ activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti-inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL. The analgesic effects of ROL were evaluated using the Von Frey and Hargreaves tests. Immunofluorescence staining was used to determine the number of c-Fos immunoreactive neurons, and the expression of spinal astrocytes and microglial activation on day 14 after tumor cell inoculation. Enzyme‑linked immunosorbent assay (ELISA) was used to detect the expression of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α] and chemokines (CCL2), and western blot analysis was then used to examine the spinal phosphodiesterase 4 (PDE4), ionized calcium binding adapter molecule-1 (IBA-1) and JNK levels on day 14 after tumor cell inoculation. The results revealed that ROL exerted a short-term analgesic effect in a dose-dependent manner, and consecutive daily injections of ROL exerted continuous analgesic effects. In addition, spinal ‘neuron‑astrocytic’ activation was suppressed and was associated with the downregulation of spinal IL-1β, IL-6 and TNF-α expression, and the inhibition of PDE4B and JNK levels in the spine was also observed. In addition, the level of CCL2 was decreased in the rats with BCP. The JNK inhibitor, SP600125, decreased CCL2 expression and attenuated pain behavior. Following co-treatment with ROL and SP600125, no significant increases in thermal hyperalgesia and CCL2 expression were observed compared with the ROL group. Thus, our findings suggest that the analgesic effects of ROL in BCP are mainly mediated through the inhibition of ‘neuron‑astrocytic’ activation, which occurs via the suppression of spinal JNK/CCL2 signaling.

View Figures

View References

1	Lozano-Ondoua AN, Symons-Liguori AM and Vanderah TW: Cancer-induced bone pain: Mechanisms and models. Neurosci Lett. 557:52–59. 2013. View Article : Google Scholar : PubMed/NCBI
2	Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A and Kaasa S: Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review. Pain. 153:359–365. 2012. View Article : Google Scholar
3	Mantyh PW: Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci. 7:797–809. 2006. View Article : Google Scholar : PubMed/NCBI
4	Ji RR, Berta T and Nedergaard M: Glia and pain: Is chronic pain a gliopathy? Pain. 154(Suppl 1): S10–S28. 2013. View Article : Google Scholar : PubMed/NCBI
5	Yang Y, Li H, Li TT, Luo H, Gu XY, Lü N, Ji RR and Zhang YQ: Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18. J Neurosci. 35:7950–7963. 2015. View Article : Google Scholar : PubMed/NCBI
6	Remeniuk B, Sukhtankar D, Okun A, Navratilova E, Xie JY, King T and Porreca F: Behavioral and neurochemical analysis of ongoing bone cancer pain in rats. Pain. 156:1864–1873. 2015. View Article : Google Scholar : PubMed/NCBI
7	Oprée A and Kress M: Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: Effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci. 20:6289–6293. 2000.PubMed/NCBI
8	Chichorro JG, Lorenzetti BB and Zampronio AR: Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. Br J Pharmacol. 141:1175–1184. 2004. View Article : Google Scholar : PubMed/NCBI
9	Zhou L, Huang J, Gao J, Zhang G and Jiang J: NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats. Cell Immunol. 287:86–90. 2014. View Article : Google Scholar : PubMed/NCBI
10	Guo W, Miyoshi K, Dubner R, Gu M, Li M, Liu J, Yang J, Zou S, Ren K, Noguchi K and Wei F: Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade. Mol Pain. 10:352014. View Article : Google Scholar : PubMed/NCBI
11	Wang XW, Hu S, Mao-Ying QL, Li Q, Yang CJ, Zhang H, Mi WL, Wu GC and Wang YQ: Activation of c-jun N-terminal kinase in spinal cord contributes to breast cancer induced bone pain in rats. Mol Brain. 5:212012. View Article : Google Scholar : PubMed/NCBI
12	Tang J, Zhu C, Li ZH, Liu XY, Sun SK, Zhang T, Luo ZJ, Zhang H and Li WY: Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain. J Neuroinflammation. 12:572015. View Article : Google Scholar : PubMed/NCBI
13	Houslay MD and Adams DR: PDE4 cAMP phosphodiesterases: Modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 370:1–18. 2003. View Article : Google Scholar
14	Pearse DD and Hughes ZA: PDE4B as a microglia target to reduce neuroinflammation. Glia. 64:1698–1709. 2016. View Article : Google Scholar : PubMed/NCBI
15	Kumar A, Jain NK and Kulkarni SK: Analgesic and anti-inflammatory effects of phosphodiesterase inhibitors. Indian J Exp Biol. 38:26–30. 2000.
16	Francischi JN, Yokoro CM, Poole S, Tafuri WL, Cunha FQ and Teixeira MM: Anti-inflammatory and analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis. Eur J Pharmacol. 399:243–249. 2000. View Article : Google Scholar : PubMed/NCBI
17	Kim HK, Kwon JY, Yoo C and Abdi S: The analgesic effect of rolipram, a phosphodiesterase 4 inhibitor, on chemotherapy-induced neuropathic pain in rats. Anesth Analg. 121:822–828. 2015. View Article : Google Scholar : PubMed/NCBI
18	Rock EM, Benzaquen J, Limebeer CL and Parker LA: Potential of the rat model of conditioned gaping to detect nausea produced by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. Pharmacol Biochem Behav. 91:537–541. 2009. View Article : Google Scholar
19	Sanna MD, Ghelardini C and Galeotti N: Blockade of the spinal BDNF-activated JNK pathway prevents the development of anti-retroviral-induced neuropathic pain. Neuropharmacology. 105:543–552. 2016. View Article : Google Scholar : PubMed/NCBI
20	Zhang Q, Wang J, Duan MT, Han SP, Zeng XY and Wang JY: NF-κB, ERK, p38 MAPK and JNK contribute to the initiation and/or maintenance of mechanical allodynia induced by tumor necrosis factor-alpha in the red nucleus. Brain Res Bull. 99:132–139. 2013. View Article : Google Scholar : PubMed/NCBI
21	Hu XM, Liu YN, Zhang HL, Cao SB, Zhang T, Chen LP and Shen W: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs-mediated neuroinflammation in bone cancer rats. J Neurochem. 132:452–463. 2015. View Article : Google Scholar
22	Wu HH, Yin JB, Zhang T, Cui YY, Dong YL, Chen GZ and Wang W: Inhibiting spinal neuron-astrocytic activation correlates with synergistic analgesia of dexmedetomidine and ropivacaine. PLoS One. 9:e923742014. View Article : Google Scholar : PubMed/NCBI
23	Liu S, Liu YP, Song WB and Song XJ: EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord. Pain. 154:2823–2835. 2013. View Article : Google Scholar : PubMed/NCBI
24	Dixon WJ: Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol. 20:441–462. 1980. View Article : Google Scholar : PubMed/NCBI
25	Hargreaves K, Dubner R, Brown F, Flores C and Joris J: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 32:77–88. 1988. View Article : Google Scholar : PubMed/NCBI
26	Hamm RJ, Pike BR, O'Dell DM, Lyeth BG and Jenkins LW: The rotarod test: An evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma. 11:187–196. 1994. View Article : Google Scholar : PubMed/NCBI
27	Mei XP, Zhang H, Wang W, Wei YY, Zhai MZ, Wang W, Xu LX and Li YQ: Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain. J Neuroinflammation. 8:62011. View Article : Google Scholar : PubMed/NCBI
28	Gao YJ and Ji RR: Activation of JNK pathway in persistent pain. Neurosci Lett. 437:180–183. 2008. View Article : Google Scholar : PubMed/NCBI
29	Li ZY, Zhang YP, Zhang J, Zhang SB, Li D, Huang ZZ and Xin WJ: The possible involvement of JNK activation in the spinal dorsal horn in bortezomib-induced allodynia: the role of TNF-α and IL-1β. J Anesth. 30:55–63. 2016. View Article : Google Scholar
30	Wang ZZ, Zhang Y, Liu YQ, Zhao N, Zhang YZ, Yuan L, An L, Li J, Wang XY, Qin JJ, et al: RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects. Br J Pharmacol. 168:1001–1014. 2013. View Article : Google Scholar :
31	García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J and Franco R: Phosphodiesterases as therapeutic targets for Alzheimer's disease. ACS Chem Neurosci. 3:832–844. 2012. View Article : Google Scholar : PubMed/NCBI
32	Wang ZZ, Yang WX, Zhang Y, Zhao N, Zhang YZ, Liu YQ, Xu Y, Wilson SP, O'Donnell JM, Zhang HT and Li YF: Phosphodiesterase-4D knock-down in the prefrontal cortex alleviates chronic unpredictable stress-induced depressive-like behaviors and memory deficits in mice. Sci Rep. 5:113322015. View Article : Google Scholar : PubMed/NCBI
33	Huang Z and Mancini JA: Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD. Curr Med Chem. 13:3253–3262. 2006. View Article : Google Scholar : PubMed/NCBI
34	Bolger GB, Dunlop AJ, Meng D, Day JP, Klussmann E, Baillie GS, Adams DR and Houslay MD: Dimerization of cAMP phosphodiesterase-4 (PDE4) in living cells requires interfaces located in both the UCR1 and catalytic unit domains. Cell Signal. 27:756–769. 2015. View Article : Google Scholar :
35	Christiansen SH, Selige J, Dunkern T, Rassov A and Leist M: Combined anti-inflammatory effects of β2-adrenergic agonists and PDE4 inhibitors on astrocytes by upregulation of intracellular cAMP. Neurochem Int. 59:837–846. 2011. View Article : Google Scholar : PubMed/NCBI
36	Ji Q, Di Y, He X, Liu Q, Liu J, Li W and Zhang L: Intrathecal injection of phosphodiesterase 4B-specific siRNA attenuates neuropathic pain in rats with L5 spinal nerve ligation. Mol Med Rep. 13:1914–1922. 2016.
37	Nunes AR, Sample V, Xiang YK, Monteiro EC, Gauda E and Zhang J: Effect of oxygen on phosphodiesterases (PDE) 3 and 4 isoforms and PKA activity in the superior cervical ganglia. Adv Exp Med Biol. 758:287–294. 2012. View Article : Google Scholar : PubMed/NCBI
38	Perez-Aso M, Montesinos MC, Mediero A, Wilder T, Schafer PH and Cronstein B: Apremilast, a novel phosphodiesterase 4 (PDE4) inhibitor, regulates inflammation through multiple cAMP downstream effectors. Arthritis Res Ther. 17:2492015. View Article : Google Scholar : PubMed/NCBI
39	Old EA, Clark AK and Malcangio M: The role of glia in the spinal cord in neuropathic and inflammatory pain. Handb Exp Pharmacol. 227:145–170. 2015. View Article : Google Scholar : PubMed/NCBI
40	Alfonso Romero-Sandoval E and Sweitzer S: Nonneuronal central mechanisms of pain: Glia and immune response. Prog Mol Biol Transl Sci. 131:325–358. 2015. View Article : Google Scholar : PubMed/NCBI
41	Romero-Alejo E, Puig MM and Romero A: Inhibition of astrocyte activation is involved in the prevention of postoperative latent pain sensitization by ketamine and gabapentin in mice. J Pharmacol Pharmacother. 7:22–24. 2016. View Article : Google Scholar : PubMed/NCBI
42	Li W, Zhang Y, Xing C and Zhang M: Tanshinone IIA represses inflammatory response and reduces radiculopathic pain by inhibiting IRAK-1 and NF-κB/p38/JNK signaling. Int Immunopharmacol. 28:382–389. 2015. View Article : Google Scholar : PubMed/NCBI
43	Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q and Ji RR: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 29:4096–4108. 2009. View Article : Google Scholar : PubMed/NCBI
44	Lu Y, Jiang BC, Cao DL, Zhang ZJ, Zhang X, Ji RR and Gao YJ: TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain. 155:2618–2629. 2014. View Article : Google Scholar : PubMed/NCBI
45	Lu C, Liu Y, Sun B, Sun Y, Hou B, Zhang Y, Ma Z and Gu X: Intrathecal injection of JWH-015 attenuates bone cancer pain via time-dependent modification of pro-inflammatory cytokines expression and astrocytes activity in spinal cord. Inflammation. 38:1880–1890. 2015. View Article : Google Scholar : PubMed/NCBI
46	Pillarisetti S: Targeting interleukin-1β for pain. CNS Neurol Disord Drug Targets. 10:571–575. 2011. View Article : Google Scholar : PubMed/NCBI
47	Narita M, Shimamura M, Imai S, Kubota C, Yajima Y, Takagi T, Shiokawa M, Inoue T, Suzuki M and Suzuki T: Role of interleukin-1beta and tumor necrosis factor-alpha-dependent expression of cyclooxygenase-2 mRNA in thermal hyperalgesia induced by chronic inflammation in mice. Neuroscience. 152:477–486. 2008. View Article : Google Scholar : PubMed/NCBI
48	Pevida M, González-Rodríguez S, Lastra A, García-Suárez O, Hidalgo A, Menéndez L and Baamonde A: Involvement of spinal chemokine CCL2 in the hyperalgesia evoked by bone cancer in mice: A role for astroglia and microglia. Cell Mol Neurobiol. 34:143–156. 2014. View Article : Google Scholar