Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats

Citation
S. Begon et al., Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats, BR J PHARM, 134(6), 2001, pp. 1227-1236
Citations number
67
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
134
Issue
6
Year of publication
2001
Pages
1227 - 1236
Database
ISI
SICI code
0007-1188(200111)134:6<1227:ROSNRP>2.0.ZU;2-D
Abstract
1 Magnesium (Mg)-deficient rats develop a mechanical hyperalgesia which is reversed by a N-Methyl-D-Aspartate (NMDA) receptor antagonist. Given that f unctioning of this receptor-channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in tur n trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non-NMDA receptors a s well as compounds interfering with the functioning of intracellular secon d messengers for effects on hyperalgesia in Mg-deficient rats. 2 Hyperalgesic Mg-deficient rats were administered intrathecally (10 mul) o r intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in respon se to a mechanical stimulus (paw pressure test) over 2 h. 3 Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 mu mol) as well a s NMDA receptor antagonists such as MK-801 (0.6, 6.0, 60 nmol), AP-5 (10.2, 40.6, 162.3 nmol) and DCKA (0.97, 9.7, 97 nmol) dose-dependently reversed the hyperalgesia. Chelerythrine chloride, a protein kinase C (PKC) inhibito r (1, 10.4, 104.2 nmol) and 7-NI, a specific nitric oxide (NO) synthase inh ibitor (37.5, 75, 150 mu mol kg(-1), i.p.) induced an anti-hyperalgesic eff ect in a dose-dependent manner. SR-140333 (0.15, 1.5, 15 nmol) and SR-48968 (0.17. 1.7, 17 nmol), antagonists of neurokinin receptors, produced a sign ificant, but moderate, increase in vocalization threshold. 4 These results demonstrate that Mg-deficiency induces a sensitization of n ociceptive pathways in the spinal cord which involves NMDA and non-NMDA rec eptors. Furthermore, the data is consistent with an active role of PKC, NO and, to a lesser extent substance P in the intracellular mechanisms leading to hyperalgesia.