The T-type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity.
Z944
calcium channels
dorsal horn
inflammatory pain
lamina I
neuronal excitability
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
02
03
2021
received:
16
11
2020
accepted:
05
04
2021
pubmed:
20
4
2021
medline:
22
9
2021
entrez:
19
4
2021
Statut:
ppublish
Résumé
T-type voltage-gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief. We utilized the selective and CNS-penetrant T-type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours. Voltage-clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T-type current, which was blocked by Z944. Due to this highly prevalent T-type current, Z944 potently blocked action-potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1-10 mg·kg T-type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.
Sections du résumé
BACKGROUND AND PURPOSE
T-type voltage-gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T-type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T-type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T-type channels alone may be insufficient for pain relief.
EXPERIMENTAL APPROACH
We utilized the selective and CNS-penetrant T-type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours.
KEY RESULTS
Voltage-clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T-type current, which was blocked by Z944. Due to this highly prevalent T-type current, Z944 potently blocked action-potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1-10 mg·kg
CONCLUSION AND IMPLICATIONS
T-type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.
Identifiants
pubmed: 33871884
doi: 10.1111/bph.15498
pmc: PMC8453510
doi:
Substances chimiques
Calcium Channel Blockers
0
Calcium Channels, T-Type
0
Piperidines
0
Z944
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3517-3532Subventions
Organisme : Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction
ID : 154336
Organisme : Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction
ID : 10677
Informations de copyright
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
J Neurosci. 2009 Aug 5;29(31):9668-82
pubmed: 19657020
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Physiol Rev. 2014 Jan;94(1):81-140
pubmed: 24382884
Pain. 2004 May;109(1-2):150-61
pubmed: 15082137
Nat Rev Neurosci. 2010 Dec;11(12):823-36
pubmed: 21068766
Sci Rep. 2019 Feb 28;9(1):3112
pubmed: 30816223
Int J Biochem Cell Biol. 2019 Mar;108:34-39
pubmed: 30648620
Br J Pharmacol. 2021 Sep;178(17):3517-3532
pubmed: 33871884
Channels (Austin). 2010 Nov-Dec;4(6):475-82
pubmed: 21139420
Pain Med. 2016 Mar;17(3):551-560
pubmed: 26814294
Neuron. 2014 Sep 3;83(5):1144-58
pubmed: 25189210
J Comp Neurol. 1986 Feb 1;244(1):53-71
pubmed: 3950090
Cell Rep. 2015 Jan 20;10(3):370-382
pubmed: 25600872
J Neurosci. 2006 Jan 18;26(3):851-61
pubmed: 16421305
Nat Neurosci. 2015 Aug;18(8):1081-3
pubmed: 26120961
J Peripher Nerv Syst. 2014 Oct;19 Suppl 2:S11-2
pubmed: 25269728
Mol Pain. 2019 Jan-Dec;15:1744806919836569
pubmed: 30803310
Nat Neurosci. 2018 Jun;21(6):869-880
pubmed: 29686262
J Neurophysiol. 2017 Aug 1;118(2):1394-1414
pubmed: 28566465
Nat Rev Neurosci. 2012 Dec;13(12):859-66
pubmed: 23165262
Pain. 2011 Apr;152(4):833-843
pubmed: 21349638
Pain. 2016 Jan;157(1):255-263
pubmed: 26683108
Br J Pharmacol. 2019 Dec;176 Suppl 1:S142-S228
pubmed: 31710715
Pain. 2015 Nov;156(11):2175-2183
pubmed: 26035253
Physiol Rev. 2013 Jul;93(3):961-92
pubmed: 23899559
Br J Pharmacol. 2015 Jan;172(2):532-48
pubmed: 24641546
Pain. 2003 Sep;105(1-2):159-68
pubmed: 14499432
Neuropharmacology. 2018 May 1;133:254-263
pubmed: 29407215
Front Cell Neurosci. 2018 Oct 17;12:370
pubmed: 30386213
Epilepsia. 2018 Apr;59(4):778-791
pubmed: 29468672
Pharmacology. 2017;99(3-4):196-203
pubmed: 27931022
Cell Rep. 2018 Feb 20;22(8):2216-2225
pubmed: 29466745
J Neurosci. 2020 Jan 8;40(2):283-296
pubmed: 31744861
Sci Transl Med. 2012 Feb 15;4(121):121ra19
pubmed: 22344687
Pain. 2017 Mar;158(3):417-429
pubmed: 27902567
Nat Neurosci. 2004 Feb;7(2):126-35
pubmed: 14730307
Prog Neurobiol. 2019 Nov;182:101677
pubmed: 31419467
Nat Commun. 2020 Sep 2;11(1):4395
pubmed: 32879322
Sci Rep. 2014 Feb 13;4:4094
pubmed: 24522697
PLoS One. 2015 May 14;10(5):e0127572
pubmed: 25974104
Mol Pain. 2014 Apr 16;10:26
pubmed: 24739328
Br J Pharmacol. 2020 Apr;177(8):1735-1753
pubmed: 31732978
J Neurosci. 2020 Jun 3;40(23):4439-4456
pubmed: 32341097
Biochim Biophys Acta. 2013 Jul;1828(7):1572-8
pubmed: 22885138
Pharmacology. 2010;85(5):295-300
pubmed: 20453553
Br J Pharmacol. 2020 Aug;177(16):3611-3616
pubmed: 32662875
Nature. 2019 Dec;576(7787):492-497
pubmed: 31766050
Pain. 1992 Sep;50(3):331-344
pubmed: 1454389
Nat Med. 2008 Dec;14(12):1325-32
pubmed: 19011637
Br J Pharmacol. 2011 Jun;163(3):484-95
pubmed: 21306582
EMBO J. 2005 Jan 26;24(2):315-24
pubmed: 15616581
J Neurosci. 2015 Nov 25;35(47):15505-22
pubmed: 26609149
J Neurosci. 2012 Jul 4;32(27):9374-82
pubmed: 22764245
Science. 2003 Feb 21;299(5610):1237-40
pubmed: 12595694
J Physiol. 2009 Jan 15;587(1):115-25
pubmed: 19001050
PLoS Biol. 2020 Jul 14;18(7):e3000410
pubmed: 32663219
Mol Pain. 2007 Sep 27;3:27
pubmed: 17900333
Brain. 2019 Jun 1;142(6):1535-1546
pubmed: 31135041
Br J Pharmacol. 2019 Apr;176(7):950-963
pubmed: 30714145