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This increased excitation can be blocked by the NMDA receptor (NMDAR) antagonist APV, apparently acting at NMDARs on primary afferents. Consistent with these results, electron microscopy demonstrates an increased incidence of NMDARs in substance P-containing spinal dorsal horn primary afferent terminals in opiate-tolerant rats. Moreover, superfusion of spinal slices from opiate-tolerant rats with NMDA produces a reversible increase in miniature EPSC (mEPSC) frequency in contrast to a decrease in mEPSC frequency produced by NMDA in opiate-naive slices. Finally, NMDAR antagonists inhibit the expression of opiate tolerance both in inhibiting EPSCs in spinal slices and in inhibiting behavioral nociceptive responses to heat.<\/jats:p><jats:p>NMDAR antagonists have been reported in many studies to inhibit morphine analgesic tolerance. Our studies suggest that an increase in primary afferent NMDAR expression and activity mediates a hypersensitivity to noxious stimuli and causes the inhibition of opiate efficacy, which defines tolerance.<\/jats:p>","DOI":"10.1523\/jneurosci.2530-06.2006","type":"journal-article","created":{"date-parts":[[2006,11,16]],"date-time":"2006-11-16T02:56:35Z","timestamp":1163645795000},"page":"12033-12042","source":"Crossref","is-referenced-by-count":65,"title":["Primary Afferent NMDA Receptors Increase Dorsal Horn Excitation and Mediate Opiate Tolerance in Neonatal Rats"],"prefix":"10.1523","volume":"26","author":[{"given":"Jinsong","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue A.","family":"Aicher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory W.","family":"Terman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2006,11,15]]},"reference":[{"key":"2023041303215969000_26.46.12033.1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903630405"},{"key":"2023041303215969000_26.46.12033.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00637-9"},{"key":"2023041303215969000_26.46.12033.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00530-2"},{"key":"2023041303215969000_26.46.12033.4","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050881"},{"key":"2023041303215969000_26.46.12033.5","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1152\/jn.2000.84.2.752","article-title":"NT-3 evokes an LTP-like facilitation of AMPA\/kainate receptor-mediated synaptic transmission in the neonatal rat spinal cord","volume":"84","author":"Arvanov","year":"2000","journal-title":"J Neurophysiol"},{"key":"2023041303215969000_26.46.12033.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4637-03.2004"},{"key":"2023041303215969000_26.46.12033.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00184-9"},{"key":"2023041303215969000_26.46.12033.8","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1523\/JNEUROSCI.10-06-01922.1990","article-title":"Serotonin enhances a low-voltage-activated calcium current in rat spinal motoneurons","volume":"10","author":"Berger","year":"1990","journal-title":"J Neurosci"},{"key":"2023041303215969000_26.46.12033.9","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-1-7"},{"key":"2023041303215969000_26.46.12033.10","doi-asserted-by":"publisher","DOI":"10.1038\/35047086"},{"key":"2023041303215969000_26.46.12033.11","doi-asserted-by":"publisher","DOI":"10.1007\/s002130000462"},{"key":"2023041303215969000_26.46.12033.12","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(93)90161-H"},{"key":"2023041303215969000_26.46.12033.13","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901960307"},{"key":"2023041303215969000_26.46.12033.14","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(00)00131-4"},{"key":"2023041303215969000_26.46.12033.15","first-page":"56","article-title":"Neuroplasticity. 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