Cingulate Alpha-2A Adrenoceptors Mediate the Effects of Clonidine on Spontaneous Pain Induced by Peripheral Nerve Injury

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2017 Sep 29

PMID 28955200

Citations 11

Authors

Yong-Jie Wang

Zhen-Xing Zuo

Cheng Wu

Li Liu

Zhi-Hui Feng

Xiang-Yao Li

Affiliations

Soon will be listed here.

Abstract

The anterior cingulate cortex (ACC) is an important brain area for the regulation of neuropathic pain. The α adrenoceptor is a good target for pain management. However, the role of cingulate α adrenoceptors in the regulation of neuropathic pain has been less studied. In this study, we investigated the involvement of cingulate α adrenoceptors in the regulation of neuropathic pain at different time points after peripheral nerve injury in mice. The application of clonidine, either systemically (0.5 mg/kg intraperitoneally) or specifically to the ACC, increased paw withdrawal thresholds (PWTs) and induced conditioned place preference (CPP) at day 7 after nerve injury, suggesting that cingulate α adrenoceptors are involved in the regulation of pain-like behaviors. Quantitative real-time PCR data showed that α adrenoceptors are the dominant α adrenoceptors in the ACC. Furthermore, the expression of cingulate α adrenoceptors was increased at day 3 and day 7 after nerve injury, but decreased at day 14, while no change was detected in the concentration of adrenaline or noradrenaline. BRL-44408 maleate, a selective antagonist of α adrenoceptors, was microinfused into the ACC. This blocking of cingulate α adrenoceptors activity abolished the CPP induced by clonidine (0.5 mg/kg intraperitoneally) but not the effects on PWTs at day 7. However, clonidine applied systemically or specifically to the ACC at day 14 increased the PWTs but failed to induce CPP; this negative effect was reversed by the overexpression of cingulate α adrenoceptors. These results suggest that cingulate α adrenoceptors are necessary for the analgesic effects of clonidine on spontaneous pain.

Citing Articles

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References

Rauck R, North J, Eisenach J . Intrathecal clonidine and adenosine: effects on pain and sensory processing in patients with chronic regional pain syndrome. Pain. 2015; 156(1):88-95. DOI: 10.1016/j.pain.0000000000000007. View

Davoody L, Quiton R, Lucas J, Ji Y, Keller A, Masri R . Conditioned place preference reveals tonic pain in an animal model of central pain. J Pain. 2011; 12(8):868-74. PMC: 3145044. DOI: 10.1016/j.jpain.2011.01.010. View

Bliss T, Collingridge G, Kaang B, Zhuo M . Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci. 2016; 17(8):485-96. DOI: 10.1038/nrn.2016.68. View

Li X, Ko H, Chen T, Descalzi G, Koga K, Wang H . Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science. 2010; 330(6009):1400-4. DOI: 10.1126/science.1191792. View

Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T . Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994; 53(1):55-63. DOI: 10.1016/0165-0270(94)90144-9. View

Pertovaara A . The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol. 2013; 716(1-3):2-7. DOI: 10.1016/j.ejphar.2013.01.067. View

Kim S, Nabekura J . Rapid synaptic remodeling in the adult somatosensory cortex following peripheral nerve injury and its association with neuropathic pain. J Neurosci. 2011; 31(14):5477-82. PMC: 6622722. DOI: 10.1523/JNEUROSCI.0328-11.2011. View

Hung C, Wang J, Strichartz G . Spontaneous Chronic Pain After Experimental Thoracotomy Revealed by Conditioned Place Preference: Morphine Differentiates Tactile Evoked Pain From Spontaneous Pain. J Pain. 2015; 16(9):903-12. PMC: 4556597. DOI: 10.1016/j.jpain.2015.06.006. View

Zhang L, Wang G, Ma J, Liu C, Liu X, Zhan Y . Brain-derived neurotrophic factor (BDNF) in the rostral anterior cingulate cortex (rACC) contributes to neuropathic spontaneous pain-related aversion via NR2B receptors. Brain Res Bull. 2016; 127:56-65. DOI: 10.1016/j.brainresbull.2016.08.016. View

10.

Tang J, Ko S, Ding H, Qiu C, Calejesan A, Zhuo M . Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol Pain. 2005; 1:6. PMC: 1074356. DOI: 10.1186/1744-8069-1-6. View

11.

Zuo Z, Wang Y, Liu L, Wang Y, Mei S, Feng Z . Huperzine A Alleviates Mechanical Allodynia but Not Spontaneous Pain via Muscarinic Acetylcholine Receptors in Mice. Neural Plast. 2015; 2015:453170. PMC: 4678084. DOI: 10.1155/2015/453170. View

12.

Xu H, Wu L, Wang H, Zhang X, Vadakkan K, Kim S . Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci. 2008; 28(29):7445-53. PMC: 3844787. DOI: 10.1523/JNEUROSCI.1812-08.2008. View

13.

Petrovic P, Ingvar M, Stone-Elander S, Petersson M, Hansson P . A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy. Pain. 1999; 83(3):459-470. DOI: 10.1016/S0304-3959(99)00150-5. View

14.

Pohjanoksa K, Jansson C, Luomala K, Marjamaki A, Savola J, Scheinin M . Alpha2-adrenoceptor regulation of adenylyl cyclase in CHO cells: dependence on receptor density, receptor subtype and current activity of adenylyl cyclase. Eur J Pharmacol. 1997; 335(1):53-63. DOI: 10.1016/s0014-2999(97)01154-0. View

15.

Bennett G . What is spontaneous pain and who has it?. J Pain. 2012; 13(10):921-9. DOI: 10.1016/j.jpain.2012.05.008. View

16.

Glynn C, Dawson D, Sanders R . A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain. Pain. 1988; 34(2):123-128. DOI: 10.1016/0304-3959(88)90157-1. View

17.

Qu C, King T, Okun A, Lai J, Fields H, Porreca F . Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy. Pain. 2011; 152(7):1641-1648. PMC: 3389793. DOI: 10.1016/j.pain.2011.03.002. View

18.

King T, Qu C, Okun A, Melemedjian O, Mandell E, Maskaykina I . Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain. Pain. 2012; 153(6):1263-1273. PMC: 3358498. DOI: 10.1016/j.pain.2012.03.006. View

19.

Liu S, Zhang M, Cheng L, Shi J, Lu J, Zhuo M . Long-term upregulation of cortical glutamatergic AMPA receptors in a mouse model of chronic visceral pain. Mol Brain. 2015; 8(1):76. PMC: 4653882. DOI: 10.1186/s13041-015-0169-z. View

20.

Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson A, Yarnitsky D . Neuropathic pain. Nat Rev Dis Primers. 2017; 3:17002. PMC: 5371025. DOI: 10.1038/nrdp.2017.2. View