Involvement of subtype 1 metabotropic glutamate receptors in apoptosis and caspase-7 over-expression in spinal cord of neuropathic rats.
The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. At 7 days post-CCI, only over-expression of bcl-2, nestin and GFAP mRNA was observed. Administration of AIDA reduced thermal hyperalgesia and mechanical allodynia at 3 and 7 days post-CCI; administration of JNJ16259685 reduced thermal hyperalgesia at 3 and 7 days post-CCI, but not mechanical allodynia. AIDA decreased the mRNA levels of bax, apaf-1, GFAP and caspase-7 genes. JNJ16259685 increased the mRNA levels of bcl-2 and GFAP gene, and decreased APAF-1 and caspases-7 genes. Inhibiting mGlu1 receptors also reduced TUNEL-positive profiles and immunohistochemical reactivity for caspase-7. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect. Moreover, JNJ16259685, but not the non-selective AIDA, increased astrogliosis which may account for its decreased analgesic efficacy. This study provides evidence that the contemporary and partial blockade of group I and likely ionotropic glutamate receptors may be a more suitable therapy than selective blockade of mGlu1 subtype receptors condition to decrease neuropathic pain symptoms.
Siniscalco
Dario
D
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, via S. Maria di Costantinopoli 16, 80138 Napoli, Italy. dariosin@uab.edu
Giordano
Catia
C
Fuccio
Carlo
C
Luongo
Livio
L
Ferraraccio
Franca
F
Rossi
Francesca
F
de Novellis
Vito
V
Roth
Kevin A
KA
Maione
Sabatino
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D053179:Caspase 7 / Q000096:biosynthesis*; D003251:Constriction, Pathologic; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005911:Gliosis / Q000235:genetics; D006930:Hyperalgesia / Q000473:pathology; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology; D008297:Male; D010146:Pain / Q000523:psychology; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020426:Sciatic Neuropathy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000201:enzymology / Q000502:physiology*
C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; C095756:1-aminoindan-1,5-dicarboxylic acid; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D012313:RNA; D053179:Caspase 7