ABSTRACT
Activation of intracellular signaling pathways involving p38 and p42/44 MAP kinases may contribute importantly to synaptic plasticity underlying spinal neuronal sensitization. Inhibitors of p38 or p42/44 pathways moderately attenuated responses of dorsal horn neurons evoked by mustard oil but not brush and alleviated the behavioral reflex sensitization seen following nerve injury. Activation of p38 and p42/44 MAP kinases in spinal cord ipsilateral to constriction injury was reduced by antagonists of NMDA, VPAC2 and NK2 (but not related) receptors, the glial inhibitor propentofylline and inhibitors of TNF-alpha. A VPAC2 receptor agonist enhanced p38 phosphorylation and caused behavioral reflex sensitization in naïve animals that could be blocked by co-administration of p38 inhibitor. Conversely, an NK2 receptor agonist activated p42/44 and caused behavioral sensitization that could be prevented by co-administration of p42/44 inhibitor. Thus, spinal p38 and p42/44 MAP kinases are activated in neuropathic pain states by mechanisms involving VPAC2, NK2, NMDA receptors and glial cytokine production.
Subject(s)
MAP Kinase Signaling System/physiology , Neuroglia/metabolism , Peripheral Nervous System Diseases/metabolism , Posterior Horn Cells/metabolism , Receptors, Neurokinin-2/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Animals , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Inflammation Mediators/pharmacology , MAP Kinase Signaling System/drug effects , Male , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Neuralgia/metabolism , Neuralgia/physiopathology , Neuroglia/drug effects , Neuroprotective Agents/pharmacology , Peripheral Nerve Injuries , Peripheral Nerves/metabolism , Peripheral Nerves/physiopathology , Peripheral Nervous System Diseases/physiopathology , Phosphorylation/drug effects , Physical Stimulation , Posterior Horn Cells/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Receptors, Neurokinin-2/drug effects , Receptors, Vasoactive Intestinal Peptide, Type II/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Xanthines/pharmacology , p38 Mitogen-Activated Protein Kinases/drug effects , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.
