{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:40:20Z","timestamp":1791902420377,"version":"4.3.4"},"reference-count":64,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5336","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1997,10,10]]},"abstract":"<jats:p>Substance P is released in the spinal cord in response to painful stimuli, but its role in nociceptive signaling remains unclear. When a conjugate of substance P and the ribosome-inactivating protein saporin was infused into the spinal cord, it was internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor. This treatment left responses to mild noxious stimuli unchanged, but markedly attenuated responses to highly noxious stimuli and mechanical and thermal hyperalgesia. Thus, lamina I spinal cord neurons that express the substance P receptor play a pivotal role in the transmission of highly noxious stimuli and the maintenance of hyperalgesia.<\/jats:p>","DOI":"10.1126\/science.278.5336.275","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:44:47Z","timestamp":1027763087000},"page":"275-279","source":"Crossref","is-referenced-by-count":567,"title":["Inhibition of Hyperalgesia by Ablation of Lamina I Spinal Neurons Expressing the Substance P Receptor"],"prefix":"10.1126","volume":"278","author":[{"given":"Patrick W.","family":"Mantyh","sequence":"first","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Rogers","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. 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Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Allen","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. 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Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randy S.","family":"Daughters","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A.","family":"Lappi","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. Ghilardi, Molecular Neurobiology Laboratory (151), Veterans Administration Medical Center, Minneapolis, MN 55417; and Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"J. Li, R. S. Daughters, D. A. Simone, Department of Preventive Sciences, School of Dentistry, University of Minnesota and the Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"D. A. Lappi, Advanced Targeting Systems, 1600 Faraday Avenue, Carlsbad, CA 92008, USA."},{"name":"R. G. Wiley, Neurology Service (147), Veterans Administration Medical Center, Nashville, TN 37212, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald G.","family":"Wiley","sequence":"additional","affiliation":[{"name":"P. W. Mantyh, S. D. Rogers, P. Honore, B. J. Allen, J. R. 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Biophys. Res. Commun. 129, 934 (1985);","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_1_10_3","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nbt0492-405","volume":"10","author":"Stirpe F.","year":"1992","unstructured":"Stirpe F., Barbieri L., Battelli M. G., Soria M., Lappi D. A., Biotechnology 10, 405 (1992).","journal-title":"Biotechnology"},{"key":"e_1_3_1_11_2","unstructured":"SP and endothelin-1 were obtained from Bachem (Torrence CA) RP67580 was from RBI (Natick MA) and SAP and SP-SAP were provided by Advanced Targeting Systems (San Diego CA). SAP and SP-SAP were in liquid form and sterile-filtered and in all other instances the compounds were weighed dissolved in sterile saline pipetted into microfuge tubes and frozen at \u221270\u00b0C until use. The IC 50 of these compounds was determined through 125 I-SP (Amersham Oak Park IL) binding to plasma membranes obtained from adult rat (7 to 10 weeks 250 g) spinal cord as described ["},{"key":"e_1_3_1_11_3","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1523\/JNEUROSCI.12-05-01917.1992","volume":"12","author":"Nicol G.","year":"1992","unstructured":"Nicol G., Klingberg D. K., Vasko M. R., J. Neurosci. 12, 1917 (1992)].","journal-title":"J. Neurosci."},{"key":"e_1_3_1_12_2","unstructured":"All procedures were approved by the Animal Care Committee at the VA Medical Center and the University of Minnesota. Neurons were cultured from the spinal cords of 18-day embryonic Holtzman rats (Harlan Sprague-Dawley Madison WI). The whole spinal cord was dissected out of the rat and placed in 4\u00b0C Puck's saline supplemented with 40 mM glucose 50 mM sucrose and 10 mM Hepes (DISG media pH 7.4). The spinal cords were then dissociated by trituration (15 to 20 times) through a small-bore serological pipette. The resulting cell suspension was centrifuged at 4\u00b0C for 5 min at 1500 rpm in a Sorvall RC-3B centrifuge (DuPont Newtown CT). The supernatant was removed and the pellet resuspended in Dulbecco's modified Eagle's medium (DMEM; Sigma) plus 5% equine serum and 5% calf serum (v\/v) (Hyclone Logan UT). The cell suspension was plated on poly- l -ornithine coated two-well chamber slides at a density of 100 000 cells per milliliter and incubated at 37\u00b0C with 9% CO 2 . After 4 days the mitotic inhibitors 5-fluoro-2\u2032-deoxyuridine and uridine were added. At 7 days the media was replaced with DMEM plus 10% equine serum (v\/v). The cells were incubated until 14 days after culture with media changes every fourth day. At day 14 after culture either saline SP SP-SAP conjugate or SAP was added to a final concentration of 10 \u22127 M. The cells were incubated for 12 hours with the SP-SAP or SAP compounds at which time the compounds were removed from the culture and fresh media was added. The cultures were then allowed to continue until the desired time points (2 hours or 1 4 7 and 10 days) at which time the experiment was terminated and the cells were processed for immunohistochemistry by fixing for 20 min at 22\u00b0C with 4% formalin in phosphate-buffered saline (PBS) as described (5-7)."},{"key":"e_1_3_1_13_2","unstructured":"Immunohistochemistry and fluorescent confocal microscopy were done as described (5-7) with an MRC-1024 Confocal Imaging System (Bio-Rad Boston MA) and an Olympus BH-2 microscope equipped for epifluorescence (Lake Success NY). For cell counts the spinal cords were cut in the sagittal plane whereas for immunofluorescence measurements the spinal cords were cut in either the sagittal or coronal plane. Both of the microscopes were set up as described ["},{"key":"e_1_3_1_13_3","doi-asserted-by":"crossref","first-page":"808","DOI":"10.2337\/diab.38.6.808","volume":"38","author":"Brelje T. C.","year":"1989","unstructured":"Brelje T. C., Scharp D. W., Sorenson R. L., Diabetes 38, 808 (1989);","journal-title":"Diabetes"},{"key":"e_1_3_1_13_4","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1523\/JNEUROSCI.15-01-00152.1995","volume":"15","author":"Mantyh P. W.","year":"1995","unstructured":"Mantyh P. W., et al., J. Neurosci. 15, 152 (1995);","journal-title":"J. Neurosci."},{"key":"e_1_3_1_13_5","unstructured":"]. SPR was detected by polyclonal rabbit antibody to SPR (anti-SPR) (1:5000) raised against a 15\u2013amino acid peptide sequence (SPR 393\u2013407 ) at the COOH-terminus of the rat SPR. SP was detected by polyclonal guinea pig anti-SP (1:1000). Calbindin was detected by monoclonal mouse anti-calbindin (Sigma 1:300). Microtubule-associated protein (MAP-2) was detected by monoclonal mouse anti\u2013MAP-2 (Sigma 1:750). Choline acetyltransferase (ChAT) was detected by monoclonal mouse anti-ChAT (Chemicon 1:500). Glial fibrillary acidic protein was detected by polyclonal rabbit anti-GFAP (DAKO 1:450). OX-42 was detected by a monoclonal mouse antibody (Chemicon 1:2000). Saporin was detected by polyclonal goat anti-Saporin (Advanced Targeting Systems 1:350). Secondary antibodies conjugated to fluorescent markers Cy3 (used with SPR Calbindin ChAT GFAP OX-42 and Saporin) and fluorescein isothiocyanate (used with SP and MAP-2) (Jackson ImmunoResearch Laboratories West Grove PA) were used at a dilution of 1:600 and 1:150 respectively. All primary (overnight 22\u00b0C) and secondary (3 hours 22\u00b0C) antibodies were applied in cocktails with 1% goat serum and 0.3% Triton X-100 in PBS solution. Finally the tissue sections were washed for 20 min in PBS (pH 7.4 22\u00b0C) mounted onto gelatin-coated slides and applied onto cover slips with PBS-glycerine containing 1.0% p -phenylenediamine to reduce photobleaching. To determine the number of immunofluorescent cell bodies (Table 1) we viewed the slides through a 1.0-cm 2 eyepiece grid which was divided into 100 1 mm by 1 mm units and counted the total number of immunofluorescent cell bodies per unit area. To calculate SPR immunofluorescence intensity we obtained images of the 60-\u03bcm-thick tissue sections with the Bio-Rad MRC1024 laser-scanning confocal fluorescent-imaging system and analyzed them using NIH Image 1.7 software."},{"key":"e_1_3_1_14_2","unstructured":"Animals were anesthetized with an intramuscular injection of ketamine (100 mg\/kg) and acepromazine (1 mg\/kg) and placed in a stereotaxic frame. An 8.5-cm length of PE-10 tubing (inner diameter 0.28 mm; outer diameter 0.61 mm) serving as an inflow cannula was inserted into the subarachnoid space through an incision in the atlanto-occipital membrane. The cannula terminated in the caudal region of the lumbar enlargement (approximately L4). The spinal cord was superfused with 10 \u03bcl of either saline or 5.0 \u00d7 10 \u22126 M SP SAP or SP-SAP followed by a 5 \u03bcl saline flush with a 25-\u03bcl Hamilton syringe. Five minutes after spinal superfusion the cannula was carefully withdrawn and the wound closed with 3-0 silk sutures."},{"key":"e_1_3_1_15_2","unstructured":"Measurements of nocifensive behavior and hyperalgesia produced by intraplantar injection of capsaicin were obtained as described ["},{"key":"e_1_3_1_15_3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0304-3959(96)03104-1","volume":"67","author":"Gilchrist H. D.","year":"1996","unstructured":"Gilchrist H. D., Allard B. L., Simone D. A., Pain 67, 179 (1996);","journal-title":"Pain"},{"key":"e_1_3_1_15_4","unstructured":"]. We and most other pain researchers define hyperalgesia as an increase in withdrawal responses. The capsaicin model of hyperalgesia used in the present experiments was chosen as it has been well characterized it produces hyperalgesia in humans and it is the only model of hyperalgesia that can be used in parallel animal and human studies. Capsaicin (Sigma) was dissolved in a vehicle of 7.5% polyxyethylene sorbitan monooleate (Tween-80) and saline and given into the plantar surface of one hindpaw. Each animal received one injection of 10 \u03bcg in a volume of 10 \u03bcl. The duration of nocifensive behavior defined as lifting and guarding the injected paw was measured for the first 5 min after injection. Withdrawal responses to heat were determined by means of a previously described procedure ["},{"key":"e_1_3_1_15_5","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90026-7"},{"key":"e_1_3_1_15_6","unstructured":"]. Rats were placed under a nonbinding cage on a 3-mm-thick glass plate that was elevated to allow maneuvering of a radiant heat source from below. Controlled radiant heat stimuli were applied to the plantar surface of the hindpaw by means of a 50-W light bulb placed in a custom-built case. The start of each trial activated a timer and withdrawal latencies to the nearest 0.1 s were measured automatically by a photocell that terminated each trial and stopped the timer upon withdrawal of the paw. Four stimuli spaced at least 1 min apart were applied to each hindpaw. Withdrawal latency for each paw was defined as the mean latency of the last three trials. The intensity of the heat was adjusted and maintained to produce withdrawal latencies of about 12 s under normal conditions. Heat hyperalgesia was defined functionally as a decrease in the withdrawal latency. To measure withdrawal responses to mechanical stimuli we placed rats under a clear plastic cage on an elevated plastic mesh floor (1-cm 2 perforations). A von Frey monofilament with a bending force of 95.0 mN was applied to the plantar surface from below the floor. The stimulus was applied 10 times each for a duration of 1 to 2 s at random locations on the plantar surface. The frequency was determined for each hindpaw. Mechanical hyperalgesia was defined as an increase in withdrawal response frequency."},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0304-3959(96)03104-1","volume":"67","author":"Gilchrist H. D.","year":"1996","unstructured":"Gilchrist H. D., Allard B., Simone D. 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Cell Biol."},{"key":"e_1_3_1_22_8","first-page":"499","volume":"274","author":"Wu-Wong J. R.","year":"1995","unstructured":"Wu-Wong J. R., Chiou W. J., Magnuson S. R., Opgenorth T. J., J. Pharmacol. Exp. Ther. 274, 499 (1995).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1093\/bja\/75.2.186","volume":"75","author":"Munglani R.","year":"1995","unstructured":"Munglani R., Hunt S. P., Br. J. Anaesth. 75, 186 (1995);","journal-title":"Br. J. Anaesth."},{"key":"e_1_3_1_23_3","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1399-6576.1997.tb04623.x","volume":"41","author":"Yaksh T. L.","year":"1997","unstructured":"Yaksh T. L., Acta Anaesthesiol. Scand. 41, 94 (1997).","journal-title":"Acta Anaesthesiol. Scand."},{"key":"e_1_3_1_24_2","doi-asserted-by":"crossref","unstructured":"B. M. Cox Handbook of Experimental Pharmacology: Opioids (Springer-Verlag Berlin 1993) p. 145;","DOI":"10.1007\/978-3-642-77460-7_8"},{"key":"e_1_3_1_24_3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/bja\/75.2.193","volume":"75","author":"Dickenson A. H.","year":"1995","unstructured":"Dickenson A. H., Br. J. Anaesth. 75, 193 (1995);","journal-title":"Br. J. Anaesth."},{"key":"e_1_3_1_24_4","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/383759a0","volume":"383","author":"Iversen L. L.","year":"1996","unstructured":"Iversen L. L., Nature 383, 759 (1996) .","journal-title":"Nature"},{"key":"e_1_3_1_25_2","unstructured":"We thank S. Vigna for antibody to SPR and J. Maggio for antibody to SP and A. Georgopoulos M. Nichols and S. Vigna for helpful suggestions and critical reading of the manuscript. Supported by NIH grants NS23970 NS31223 and MH56368 a Veterans Administration Merit Review and the Association Fran\u00e7aise pour la Recherche en Th\u00e9rapeutique."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.278.5336.275","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:45:41Z","timestamp":1705121141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.278.5336.275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,10,10]]},"references-count":64,"journal-issue":{"issue":"5336","published-print":{"date-parts":[[1997,10,10]]}},"alternative-id":["10.1126\/science.278.5336.275"],"URL":"https:\/\/doi.org\/10.1126\/science.278.5336.275","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,10,10]]}}}