Altered nociception in mice with genetically induced hypoglutamatergic tone.
Extensive pharmacological evidence supports the idea that glutamate plays a key role in both acute and chronic pain. In the present study, we investigated the implication of the excitatory amino acid in physiological nociception by using mutant mice deficient in phosphate-activated glutaminase type 1 (GLS1), the enzyme that synthesizes glutamate in central glutamatergic neurons. Because homozygous GLS1-/- mutants die shortly after birth, assays for assessing mechanical, thermal and chemical (formalin) nociception were performed on heterozygous GLS1+/- mutants, which present a clear-cut decrease in glutamate synthesis in central neurons. As compared to paired wild-type mice, adult male GLS1+/- mutants showed decreased responsiveness to mechanical (von Frey filament and tail-pressure, but not tail-clip, tests) and thermal (Hargreaves' plantar, tail-immersion and hot-plate tests) nociceptive stimuli. Genotype-related differences were also found in the formalin test for which GLS1+/- mice exhibited marked decreases in the nociceptive responses (hindlimb lift, lick and flinch) during both phase 1 (0-5 min) and phase 2 (16-45 min) after formalin injection. On the other hand, acute treatment with memantine (1mg/kg i.p.), an uncompetitive antagonist at NMDA glutamate receptors, reduced nociception responses in wild-type but not GLS1+/- mice. Conversely, antinociceptive response to acute administration of a low dose (1mg/kg s.c.) of morphine was significantly larger in GLS1+/- mutants versus wild-type mice. Our findings indicate that genetically driven hypoactivity of central glutamatergic neurotransmission renders mice hyposensitive to nociceptive stimulations, and promotes morphine antinociception, further emphasizing the critical role of glutamate in physiological nociception and its opioid-mediated control.
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France.
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Kayser
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France.
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Viguier
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France.
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Melfort
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France; Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France.
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Bourgoin
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France; Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France.
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Hamon
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France; Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris F-75013, France; Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France. Electronic address: justine.masson@inserm.fr.
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Masson
D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005971:Glutamates / Q000378:metabolism / Q000502:physiology*; D005972:Glutaminase / Q000235:genetics*; D006358:Hot Temperature; D008297:Male; D008559:Memantine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000008:administration & dosage; D059225:Nociception / Q000502:physiology*; D010641:Phenotype; D010812:Physical Stimulation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C574238:GLS1 protein, mouse; D005972:Glutaminase; D008559:Memantine
formalin; memantine; morphine; nociceptive tests; phosphate-activated glutaminase type 1