Role of spinal NMDA receptors, protein kinase C and nitric oxide synthase in the hyperalgesia induced by magnesium deficiency in rats.
1. 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. 2. Hyperalgesic Mg-deficient rats were administered intrathecally (10 microl) 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. 3. Intrathecal administration of MgSO4 (1.6, 3.2, 4.8, 6.6 micromol) 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 micromol x 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. 4. 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.
Begon
S
S
EMI INSERM/UdA 9904-Pharmacologie Fondamentale et Clinique de la Douleur, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, B.P. 38, 63001 Clermont-Ferrand, Cedex 1, France.
Pickering
G
G
Eschalier
A
A
Mazur
A
A
Rayssiguier
Y
Y
Dubray
C
C
D015763:2-Amino-5-phosphonovalerate / Q000493:pharmacokinetics; D000470:Alkaloids; D000700:Analgesics / Q000493:pharmacokinetics; D000818:Animals; D053119:Benzophenanthridines; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics*; D006930:Hyperalgesia / Q000139:chemically induced; D007191:Indazoles / Q000493:pharmacokinetics; D007278:Injections, Spinal; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008278:Magnesium Sulfate / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010147:Pain Measurement; D010617:Phenanthridines / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013131:Spine / Q000378:metabolism*
D000470:Alkaloids; D000700:Analgesics; D053119:Benzophenanthridines; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D010617:Phenanthridines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D008278:Magnesium Sulfate; D015763:2-Amino-5-phosphonovalerate; C016299:chelerythrine; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; C080122:7-nitroindazole