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Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats
Author(s) -
Begon Sophie,
Pickering Gisèle,
Eschalier Alain,
Mazur André,
Rayssiguier Yves,
Dubray Claude
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704354
Subject(s) - nmda receptor , hyperalgesia , nitric oxide synthase , chemistry , pharmacology , chelerythrine , receptor , endocrinology , medicine , protein kinase c , nitric oxide , nociception , signal transduction , biochemistry
Magnesium (Mg)‐deficient rats develop a mechanical hyperalgesia which is reversed by a N‐Methyl‐ D ‐Aspartate (NMDA) receptor antagonist. Given that functioning of this receptor‐channel is modulated by Mg, we wondered whether facilitated activation of NMDA receptors in Mg deficiency state may in turn trigger a cascade of specific intracellular events present in persistent pain. Hence, we tested several antagonists of NMDA and non‐NMDA receptors as well as compounds interfering with the functioning of intracellular second messengers for effects on hyperalgesia in Mg‐deficient rats. Hyperalgesic Mg‐deficient rats were administered intrathecally (10 μl) or intraperitoneally with different antagonists. After drug injection, pain sensitivity was evaluated by assessing the vocalization threshold in response to a mechanical stimulus (paw pressure test) over 2 h. Intrathecal administration of MgSO 4 (1.6, 3.2, 4.8, 6.6 μmol) as well as 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) inhibitor (1, 10.4, 104.2 nmol) and 7‐NI, a specific nitric oxide (NO) synthase inhibitor (37.5, 75, 150 μmol kg −1 , i.p.) induced an anti‐hyperalgesic effect 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 significant, but moderate, increase in vocalization threshold. These results demonstrate that Mg‐deficiency induces a sensitization of nociceptive pathways in the spinal cord which involves NMDA and non‐NMDA receptors. 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.British Journal of Pharmacology (2001) 134 , 1227–1236; doi: 10.1038/sj.bjp.0704354