Differential effects of NMDA and group I mGluR antagonists on both nociception and spinal cord protein kinase C translocation in the formalin test and a model of neuropathic pain in rats

Coincident with nociception, both noxious chemical stimulation of the hind paw and chronic constriction injury (CCI) of the sciatic nerve produce an i ncrease in protein kinase C (PKC) translocation in the spinal cord of rats. Noxious stimulus-induced PKC translocation likely depends on glutamate act ivity at either N-methyl-D-aspartate (NMDA) receptors or group I metabotrop ic glutamate receptors (mGluR1/5) in the spinal cord dorsal horn. This stud y compares nociceptive responses to, and the alterations in membrane-associ ated PKC, induced by noxious chemical stimulation of the hindpaw and CCI of the sciatic nerve, as well as their modulation by both NMDA and mGluR1/5 r eceptor antagonists. Three groups of rats were given a single intrathecal ( i.t.) injection of either vehicle, dizocilpine maleate (MK-801, 60 nmol), a n NMDA receptor antagonist, or (S)-4-carboxyphenylglycine (S)-4CPG, (150 nm ol), an mGluR1/5 antagonist, 10 min prior to a 50 mul of 2.5% formalin inje ction into the ventral surface of one hind paw. Another three groups of rat s were given twice daily injections of either vehicle, MK-801 (30 nmol) or (S)-4CPG (90 nmol) i.t. for 5 days starting 30 min before CCI or sham injur y of the sciatic nerve. Nociceptive responses were assessed for a 60 min pe riod after the formalin injection in the first three groups, and tests of m echanical and cold allodynia were performed on days 4, 8, 12 and 16 after C CI for the latter three groups. Furthermore, changes in the levels of membr aneassociated PKC, as assayed by quantitative autoradiography of the specif ic binding of [H-3]-phorbol 12,13-dibutyrate ([H-3]-PDBu) in the dorsal hor n of the lumbar spinal cord sections, were assessed in formalin-injected ra ts (at 5, 25 and 60 min) and in neuropathic rats 5 days after CCI, treated (as above) with vehicle, MK-801 or (S)-4CPG. The results indicate that i.t. treatment with MK-801 significantly reduced nociceptive scores in the form alin test and also produced a significant suppression of formalin-induced i ncreases in [H-3]-PDBu binding in laminae I-II, III-VI and X of the lumbar spinal cord. In contrast, i.t. treatment with (S)-4CPG failed to significan tly affect either nociceptive behaviours in the formalin test or formalin-I nduced increases in [3H]-PDBu binding in laminae I-II and III-VI of the lum bar spinal cord. On the other hand, Lt. treatment with either MK-801 or (S) -4CPG produced a significant reduction in mechanical and cold hypersensitiv ity, as well as [H-3]-PDBu binding in laminae I-II and III-VI of the lumbar spinal cord, after CCL These results suggest that while NMDA, but not mGlu R1/5, receptors are involved in translocation of PKC and nociception in a m odel of persistent acute pain, both types of receptors influence the transl ocation of PKC in dorsal horn and mechanical and cold allodynia in a model of chronic neuropathic pain. (C) 2001 International Association for the Stu dy of Pain. Published by Elsevier Science B.V. All rights reserved.