CaMKIIα May Modulate Fentanyl-induced Hyperalgesia Via a CeLC-PAG-RVM-spinal Cord Descending Facilitative Pain Pathway in Rats

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 May 11

PMID 28489932

Citations 9

Authors

Zhen Li

Pingping Yin

Jian Chen

Shenglan Jin

Jieqiong Liu

Fang Luo

Affiliations

Soon will be listed here.

Abstract

Each of the lateral capsular division of central nucleus of amygdala(CeLC), periaqueductal gray (PAG), rostral ventromedial medulla(RVM) and spinal cord has been proved to contribute to the development of opioid-induced hyperalgesia(OIH). Especially, Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) in CeLC and spinal cord seems to play a key role in OIH modulation. However, the pain pathway through which CaMKIIα modulates OIH is not clear. The pathway from CeLC to spinal cord for this modulation was explored in the present study. Mechanical and thermal hyperalgesia were tested by von Frey test or Hargreaves test, respectively. CaMKIIα activity (phospho-CaMKIIα, p-CaMKIIα) was evaluated by western blot analysis. CaMKIIα antagonist (KN93) was micro-infused into CeLC, spinal cord or PAG, respectively, to evaluate its effect on behavioral hyperalgesia and p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord. Then the underlying synaptic mechanism was explored by recording miniature excitatory postsynaptic currents (mEPSCs) on PAG slices using whole-cell voltage-clamp methods. Results showed that inhibition of CeLC, PAG or spinal CaMKIIα activity respectively by KN93, reversed both mechanical and thermal hyperalgesia. Microinjection of KN93 into CeLC decreased p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord; while intrathecal KN93 can only block spinal but not CeLC CaMKIIα activity. KN93 injected into PAG just decreased p-CaMKIIα expression in PAG, RVM and spinal cord, but not in the CeLC. Similarly, whole-cell voltage-clamp recording found the frequency and amplitude of mEPSCs in PAG cells were decreased by KN93 added in PAG slice or micro-infused into CeLC in vivo. These results together with previous findings suggest that CaMKIIα may modulate OIH via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway.

Citing Articles

Restoration of the Activity of the Prefrontal Cortex to the Nucleus Accumbens Core Pathway Relieves Fentanyl-Induced Hyperalgesia in Male Rats.

Luo Q, Luo J, Wang X, Gan S J Pain Res. 2024; 17:1243-1256.

PMID: 38524691 PMC: 10961020. DOI: 10.2147/JPR.S442765.

Projections from infralimbic medial prefrontal cortex glutamatergic outputs to amygdala mediates opioid induced hyperalgesia in male rats.

Cui L, Wang X, Liu H, Luo F, Li C Mol Pain. 2024; 20:17448069241226960.

PMID: 38172075 PMC: 10851759. DOI: 10.1177/17448069241226960.

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats.

Wang X, Gan S, Zhang Z, Zhu P, Li C, Luo F Mol Neurobiol. 2023; 60(5):2553-2571.

PMID: 36689134 DOI: 10.1007/s12035-023-03218-w.

SCFAs Ameliorate Chronic Postsurgical Pain-Related Cognition Dysfunction via the ACSS2-HDAC2 Axis in Rats.

Li Z, Sun T, He Z, Li Z, Zhang W, Wang J Mol Neurobiol. 2022; 59(10):6211-6227.

PMID: 35902549 PMC: 9463230. DOI: 10.1007/s12035-022-02971-8.

Amygdala Metabotropic Glutamate Receptor 1 Influences Synaptic Transmission to Participate in Fentanyl-Induced Hyperalgesia in Rats.

Bai T, Chen H, Hu W, Liu J, Lin X, Chen S Cell Mol Neurobiol. 2022; 43(3):1401-1412.

PMID: 35798932 PMC: 11414450. DOI: 10.1007/s10571-022-01248-x.

References

Chen Y, Yang C, Wang Z . Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia. J Neurosci. 2010; 30(1):38-46. PMC: 2821163. DOI: 10.1523/JNEUROSCI.4346-09.2010. View

Lee H, Yeomans D . Opioid induced hyperalgesia in anesthetic settings. Korean J Anesthesiol. 2014; 67(5):299-304. PMC: 4252340. DOI: 10.4097/kjae.2014.67.5.299. View

Zhou H, Chen S, Chen H, Pan H . Opioid-induced long-term potentiation in the spinal cord is a presynaptic event. J Neurosci. 2010; 30(12):4460-6. PMC: 2852319. DOI: 10.1523/JNEUROSCI.5857-09.2010. View

Rosen A, Zhang Y, Lund I, Lundeberg T, Yu L . Substance P microinjected into the periaqueductal gray matter induces antinociception and is released following morphine administration. Brain Res. 2004; 1001(1-2):87-94. DOI: 10.1016/j.brainres.2003.11.060. View

Price T, Jeske N, Flores C, Hargreaves K . Pharmacological interactions between calcium/calmodulin-dependent kinase II alpha and TRPV1 receptors in rat trigeminal sensory neurons. Neurosci Lett. 2005; 389(2):94-8. PMC: 1892278. DOI: 10.1016/j.neulet.2005.07.029. View

Bee L, Dickenson A . Rostral ventromedial medulla control of spinal sensory processing in normal and pathophysiological states. Neuroscience. 2007; 147(3):786-93. DOI: 10.1016/j.neuroscience.2007.05.004. View

Meng I, Harasawa I . Chronic morphine exposure increases the proportion of on-cells in the rostral ventromedial medulla in rats. Life Sci. 2007; 80(20):1915-20. PMC: 2736558. DOI: 10.1016/j.lfs.2007.02.022. View

Chen Y, Li A, Yeh T, Chou A, Wang H . Nocistatin and nociceptin exert opposite effects on the excitability of central amygdala nucleus-periaqueductal gray projection neurons. Mol Cell Neurosci. 2008; 40(1):76-88. DOI: 10.1016/j.mcn.2008.09.003. View

Hu J, Wang Z, Guo Y, Zhang X, Xu Z, Liu S . A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain. Mol Pain. 2009; 5:71. PMC: 2803476. DOI: 10.1186/1744-8069-5-71. View

10.

Garzon J, Rodriguez-Munoz M, Vicente-Sanchez A, Bailon C, Martinez-Murillo R, Sanchez-Blazquez P . RGSZ2 binds to the neural nitric oxide synthase PDZ domain to regulate mu-opioid receptor-mediated potentiation of the N-methyl-D-aspartate receptor-calmodulin-dependent protein kinase II pathway. Antioxid Redox Signal. 2011; 15(4):873-87. DOI: 10.1089/ars.2010.3767. View

11.

Sanchez-Blazquez P, Rodriguez-Munoz M, Garzon J . Mu-opioid receptors transiently activate the Akt-nNOS pathway to produce sustained potentiation of PKC-mediated NMDAR-CaMKII signaling. PLoS One. 2010; 5(6):e11278. PMC: 2890584. DOI: 10.1371/journal.pone.0011278. View

12.

Coulombe M, Erpelding N, Kucyi A, Davis K . Intrinsic functional connectivity of periaqueductal gray subregions in humans. Hum Brain Mapp. 2016; 37(4):1514-30. PMC: 6867375. DOI: 10.1002/hbm.23117. View

13.

Mao J . Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002; 100(3):213-217. DOI: 10.1016/S0304-3959(02)00422-0. View

14.

Ferrari L, Bogen O, Levine J . Role of nociceptor αCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. J Neurosci. 2013; 33(27):11002-11. PMC: 3718370. DOI: 10.1523/JNEUROSCI.1785-13.2013. View

15.

Ossipov M, Lai J, King T, Vanderah T, Porreca F . Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers. 2005; 80(2-3):319-24. DOI: 10.1002/bip.20254. View

16.

Jiang M, Zhang W, Cheng C, Ma Z, Gu X . Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats. Pharmacol Biochem Behav. 2015; 134:35-41. DOI: 10.1016/j.pbb.2015.04.015. View

17.

Vanderah T, Suenaga N, Ossipov M, Malan Jr T, Lai J, Porreca F . Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci. 2001; 21(1):279-86. PMC: 6762454. View

18.

de Novellis V, Luongo L, Guida F, Cristino L, Palazzo E, Russo R . Effects of intra-ventrolateral periaqueductal grey palmitoylethanolamide on thermoceptive threshold and rostral ventromedial medulla cell activity. Eur J Pharmacol. 2011; 676(1-3):41-50. DOI: 10.1016/j.ejphar.2011.11.034. View

19.

Butler R, Nilsson-Todd L, Cleren C, Lena I, Garcia R, Finn D . Molecular and electrophysiological changes in the prefrontal cortex-amygdala-dorsal periaqueductal grey pathway during persistent pain state and fear-conditioned analgesia. Physiol Behav. 2011; 104(5):1075-81. DOI: 10.1016/j.physbeh.2011.05.028. View

20.

Carrasquillo Y, Gereau 4th R . Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception. J Neurosci. 2007; 27(7):1543-51. PMC: 6673749. DOI: 10.1523/JNEUROSCI.3536-06.2007. View