Transmission of chronic nociception by spinal neurons expressing the substance P receptor

Science

Volumn 286, Issue 5444, 1999, Pages 1558-1561

  Nichols, Michael L ^a,b   Allen, Brian J ^a,b   Rogers, Scott D ^a,b   Ghilardi, Joseph R ^a,b   Honore, Prisca ^a,b   Luger, Nancy M ^a,b   Finke, Matthew P ^a,b   Li, Jun ^a   Lappi, Douglas A ^c   Simone, Donald A ^a   Mantyh, Patrick W ^a,b  

^a UNIVERSITY OF MINNESOTA   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c Advanced Targeting Systems   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CAPSAICIN; CARRAGEENAN; MORPHINE; SAPORIN; SUBSTANCE P; SUBSTANCE P RECEPTOR;

ALLODYNIA; ARTICLE; CONTROLLED STUDY; HEAT SENSATION; HUMAN; HYPERALGESIA; INFLAMMATION; NEUROPATHY; NOCICEPTION; PRIORITY JOURNAL; SPINAL CORD NERVE CELL;

ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; GANGLIA, SPINAL; IMMUNOTOXINS; INFLAMMATION; LIGATION; N-GLYCOSYL HYDROLASES; NEURALGIA; PAIN; PLANT PROTEINS; POSTERIOR HORN CELLS; RATS; RECEPTORS, NEUROKININ-1; SPINAL NERVES; SUBSTANCE P; TIME FACTORS;

EID: 13044305848     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.286.5444.1558     Document Type: Article

References (27)

1. S. Arner and B. A. Meyerson, Pain 33, 11 (1988); H. L. Fields, M. Rowbotham. R. Baron, Neurobiol. Dis. 5, 209 (1998); M. Koltzenburg, Curr. Opin. Neurol. 11, 515 (1998).
2. S. Arner and B. A. Meyerson, Pain 33, 11 (1988); H. L. Fields, M. Rowbotham. R. Baron, Neurobiol. Dis. 5, 209 (1998); M. Koltzenburg, Curr. Opin. Neurol. 11, 515 (1998).
3. S. Arner and B. A. Meyerson, Pain 33, 11 (1988); H. L. Fields, M. Rowbotham. R. Baron, Neurobiol. Dis. 5, 209 (1998); M. Koltzenburg, Curr. Opin. Neurol. 11, 515 (1998).
4. D. J. Mayer, D. D. Price, D. P. Becker, Pain 1, 51 (1975); R. Dubner, D. R. Kenshalo, W. Maixner, M. C. Bushnell, J. L. Oliveras J. Neurophysiol. 62, 450 (1989); D. A. Simone et al., J. Neurophysiol. 66, 228 (1991).
5. D. J. Mayer, D. D. Price, D. P. Becker, Pain 1, 51 (1975); R. Dubner, D. R. Kenshalo, W. Maixner, M. C. Bushnell, J. L. Oliveras J. Neurophysiol. 62, 450 (1989); D. A. Simone et al., J. Neurophysiol. 66, 228 (1991).
6. D. J. Mayer, D. D. Price, D. P. Becker, Pain 1, 51 (1975); R. Dubner, D. R. Kenshalo, W. Maixner, M. C. Bushnell, J. L. Oliveras J. Neurophysiol. 62, 450 (1989); D. A. Simone et al., J. Neurophysiol. 66, 228 (1991).
7. Cell counts were performed with the neuronal nuclei marker NeuN and SPR antibodies [R. J. Mullen, C. R. Buck, A. M. Smith, Development 116, 201 (1992); J. O. Suhonen, D. A. Peterson, J. Ray, F. H. Gage, Nature 383, 624 (1996)] (i) by quantifying the total number of NeuN- and SPR-immunoreactive cells with a standard fluorescence microscope, by using the optical dissector method [R. E. Coggeshall, Trends. Neurosci. 15, 9 (1992)], and (iii) by counting the total number of NeuN- and SPR-immunoreactive cells with the Bio-Rad MRC 1024 confocal microscope in a z series of 20 μm in 2-μm steps (beginning 10 μm into the tissue section). The z series was collapsed, and the number of cells was counted with Image Pro Plus (Media Cybernetics, Silver Spring, MD). With the use of these methods, the proportion of NeuN-positive cells that were also SPR-positive ranged from 2.8 to 6.3%. for similar results, see J. L. Brown et al. [J. Comp. Neurol. 356, 327 (1995)] and N. K. Littlewood, A. J. Todd, R. C. Spike, C. Watt, and S. A. Shehab [Neuroscience 66, 597 (1995)]. n sizes = 5, 6, and 10 for saline, SAP, and SP-SAP, respectively, with averages of 3 to 7 sections per animal.
8. Cell counts were performed with the neuronal nuclei marker NeuN and SPR antibodies [R. J. Mullen, C. R. Buck, A. M. Smith, Development 116, 201 (1992); J. O. Suhonen, D. A. Peterson, J. Ray, F. H. Gage, Nature 383, 624 (1996)] (i) by quantifying the total number of NeuN- and SPR-immunoreactive cells with a standard fluorescence microscope, by using the optical dissector method [R. E. Coggeshall, Trends. Neurosci. 15, 9 (1992)], and (iii) by counting the total number of NeuN- and SPR-immunoreactive cells with the Bio-Rad MRC 1024 confocal microscope in a z series of 20 μm in 2-μm steps (beginning 10 μm into the tissue section). The z series was collapsed, and the number of cells was counted with Image Pro Plus (Media Cybernetics, Silver Spring, MD). With the use of these methods, the proportion of NeuN-positive cells that were also SPR-positive ranged from 2.8 to 6.3%. for similar results, see J. L. Brown et al. [J. Comp. Neurol. 356, 327 (1995)] and N. K. Littlewood, A. J. Todd, R. C. Spike, C. Watt, and S. A. Shehab [Neuroscience 66, 597 (1995)]. n sizes = 5, 6, and 10 for saline, SAP, and SP-SAP, respectively, with averages of 3 to 7 sections per animal.
9. Cell counts were performed with the neuronal nuclei marker NeuN and SPR antibodies [R. J. Mullen, C. R. Buck, A. M. Smith, Development 116, 201 (1992); J. O. Suhonen, D. A. Peterson, J. Ray, F. H. Gage, Nature 383, 624 (1996)] (i) by quantifying the total number of NeuN- and SPR-immunoreactive cells with a standard fluorescence microscope, by using the optical dissector method [R. E. Coggeshall, Trends. Neurosci. 15, 9 (1992)], and (iii) by counting the total number of NeuN- and SPR-immunoreactive cells with the Bio-Rad MRC 1024 confocal microscope in a z series of 20 μm in 2-μm steps (beginning 10 μm into the tissue section). The z series was collapsed, and the number of cells was counted with Image Pro Plus (Media Cybernetics, Silver Spring, MD). With the use of these methods, the proportion of NeuN-positive cells that were also SPR-positive ranged from 2.8 to 6.3%. for similar results, see J. L. Brown et al. [J. Comp. Neurol. 356, 327 (1995)] and N. K. Littlewood, A. J. Todd, R. C. Spike, C. Watt, and S. A. Shehab [Neuroscience 66, 597 (1995)]. n sizes = 5, 6, and 10 for saline, SAP, and SP-SAP, respectively, with averages of 3 to 7 sections per animal.
10. Cell counts were performed with the neuronal nuclei marker NeuN and SPR antibodies [R. J. Mullen, C. R. Buck, A. M. Smith, Development 116, 201 (1992); J. O. Suhonen, D. A. Peterson, J. Ray, F. H. Gage, Nature 383, 624 (1996)] (i) by quantifying the total number of NeuN- and SPR-immunoreactive cells with a standard fluorescence microscope, by using the optical dissector method [R. E. Coggeshall, Trends. Neurosci. 15, 9 (1992)], and (iii) by counting the total number of NeuN- and SPR-immunoreactive cells with the Bio-Rad MRC 1024 confocal microscope in a z series of 20 μm in 2-μm steps (beginning 10 μm into the tissue section). The z series was collapsed, and the number of cells was counted with Image Pro Plus (Media Cybernetics, Silver Spring, MD). With the use of these methods, the proportion of NeuN-positive cells that were also SPR-positive ranged from 2.8 to 6.3%. for similar results, see J. L. Brown et al. [J. Comp. Neurol. 356, 327 (1995)] and N. K. Littlewood, A. J. Todd, R. C. Spike, C. Watt, and S. A. Shehab [Neuroscience 66, 597 (1995)]. n sizes = 5, 6, and 10 for saline, SAP, and SP-SAP, respectively, with averages of 3 to 7 sections per animal.
11. Cell counts were performed with the neuronal nuclei marker NeuN and SPR antibodies [R. J. Mullen, C. R. Buck, A. M. Smith, Development 116, 201 (1992); J. O. Suhonen, D. A. Peterson, J. Ray, F. H. Gage, Nature 383, 624 (1996)] (i) by quantifying the total number of NeuN- and SPR-immunoreactive cells with a standard fluorescence microscope, by using the optical dissector method [R. E. Coggeshall, Trends. Neurosci. 15, 9 (1992)], and (iii) by counting the total number of NeuN- and SPR-immunoreactive cells with the Bio-Rad MRC 1024 confocal microscope in a z series of 20 μm in 2-μm steps (beginning 10 μm into the tissue section). The z series was collapsed, and the number of cells was counted with Image Pro Plus (Media Cybernetics, Silver Spring, MD). With the use of these methods, the proportion of NeuN-positive cells that were also SPR-positive ranged from 2.8 to 6.3%. for similar results, see J. L. Brown et al. [J. Comp. Neurol. 356, 327 (1995)] and N. K. Littlewood, A. J. Todd, R. C. Spike, C. Watt, and S. A. Shehab [Neuroscience 66, 597 (1995)]. n sizes = 5, 6, and 10 for saline, SAP, and SP-SAP, respectively, with averages of 3 to 7 sections per animal.
12. Y. Q. Ding, M. Takada, R. Shigemoto. N. Mizurno, Brain Res. 674, 336 (1995); G. E. Marshall, S. A. Shehab, R. C. Spike, A. J. Todd, Neuroscience 72, 255 (1996).
13. Y. Q. Ding, M. Takada, R. Shigemoto. N. Mizurno, Brain Res. 674, 336 (1995); G. E. Marshall, S. A. Shehab, R. C. Spike, A. J. Todd, Neuroscience 72, 255 (1996).
14. P. W. Mantyh et al., Science 278, 275 (1997).
15. Rats received an s.c. injection of formalin (2.5%, 50 μl) into the dorsal surface of the hind paw or the forepaw. The number of paw flinches was quantified every 5 min for 50 min after injection [D. Dubuisson and S. C. Dennis, Pain 4, 161 (1977)]. Rats receiving formalin in the forepaw were also observed for time spent licking or guarding the forepaw [B. Calvino, Physiol. Behav. 47, 907 (1990); C. A. Porro, G. Tassinari, F. Facchinetti, A. E. Panerai, G. Carli, Exp. Brain Res. 83, 549 (1991)].
16. Rats received an s.c. injection of formalin (2.5%, 50 μl) into the dorsal surface of the hind paw or the forepaw. The number of paw flinches was quantified every 5 min for 50 min after injection [D. Dubuisson and S. C. Dennis, Pain 4, 161 (1977)]. Rats receiving formalin in the forepaw were also observed for time spent licking or guarding the forepaw [B. Calvino, Physiol. Behav. 47, 907 (1990); C. A. Porro, G. Tassinari, F. Facchinetti, A. E. Panerai, G. Carli, Exp. Brain Res. 83, 549 (1991)].
17. Rats received an s.c. injection of formalin (2.5%, 50 μl) into the dorsal surface of the hind paw or the forepaw. The number of paw flinches was quantified every 5 min for 50 min after injection [D. Dubuisson and S. C. Dennis, Pain 4, 161 (1977)]. Rats receiving formalin in the forepaw were also observed for time spent licking or guarding the forepaw [B. Calvino, Physiol. Behav. 47, 907 (1990); C. A. Porro, G. Tassinari, F. Facchinetti, A. E. Panerai, G. Carli, Exp. Brain Res. 83, 549 (1991)].
18. -6 M) and were tested at 3 hours and each day for 3 days (λ-carrageenan) or 9 days (CFA) in the thermal and mechanical assays [L. Kocher, F. Anton, P. W. Reeh, H. O. Handwerker, Pain 29, 363 (1987); M. J. Millan et al., Pain 35, 299 (1988)].
19. -6 M) and were tested at 3 hours and each day for 3 days (λ-carrageenan) or 9 days (CFA) in the thermal and mechanical assays [L. Kocher, F. Anton, P. W. Reeh, H. O. Handwerker, Pain 29, 363 (1987); M. J. Millan et al., Pain 35, 299 (1988)].
20. Rats were prepared according to the method of S. H. Kim and J. M. Chung [Pain 50, 355 (1992)]. Rats were anesthetized with halothane, and the L5 and L6 spinal nerves were tightly ligated Animals were allowed to recover for 1 week.
21. The loss of lamina III neurons at 30 days observed in the present study is a result of binning the number of SPR-positive neurons in each individual lamina. Previously, neurons from laminae III to V were analyzed as one group (5). If SPR-expressing neurons in laminae III to V are combined and counted as one group, there is no significant loss of laminae III to V neurons at 30 days after infusion of SP-SAP. The delayed loss of SPR-expressing neurons in laminae IV and V compared with neurons in laminae I to III may be due to the rapid diffusion and internalization of SP-SAP in laminae I and III neurons compared with the deeper laminae IV and V neurons. In contrast, the loss of SPR-expressing neurons in laminae I, III, IV, and V all appear to have reached maximal levels at 100 days.
22. C. R. Bozic. B. Lu, U. E. Höpken, C. Gerard, N. P. Gerard, Science 273, 1722 (1996); Y. Q. Cao et al., Nature 392, 390 (1998); M. S. Kramer et al., Science 281, 1640 (1998); C. Defelipe et al., Nature 392, 394 (1998); C. A. Doyle and S. P. Hunt, Neuroscience 89, 17 (1999).
23. C. R. Bozic. B. Lu, U. E. Höpken, C. Gerard, N. P. Gerard, Science 273, 1722 (1996); Y. Q. Cao et al., Nature 392, 390 (1998); M. S. Kramer et al., Science 281, 1640 (1998); C. Defelipe et al., Nature 392, 394 (1998); C. A. Doyle and S. P. Hunt, Neuroscience 89, 17 (1999).
24. C. R. Bozic. B. Lu, U. E. Höpken, C. Gerard, N. P. Gerard, Science 273, 1722 (1996); Y. Q. Cao et al., Nature 392, 390 (1998); M. S. Kramer et al., Science 281, 1640 (1998); C. Defelipe et al., Nature 392, 394 (1998); C. A. Doyle and S. P. Hunt, Neuroscience 89, 17 (1999).
25. C. R. Bozic. B. Lu, U. E. Höpken, C. Gerard, N. P. Gerard, Science 273, 1722 (1996); Y. Q. Cao et al., Nature 392, 390 (1998); M. S. Kramer et al., Science 281, 1640 (1998); C. Defelipe et al., Nature 392, 394 (1998); C. A. Doyle and S. P. Hunt, Neuroscience 89, 17 (1999).
26. C. R. Bozic. B. Lu, U. E. Höpken, C. Gerard, N. P. Gerard, Science 273, 1722 (1996); Y. Q. Cao et al., Nature 392, 390 (1998); M. S. Kramer et al., Science 281, 1640 (1998); C. Defelipe et al., Nature 392, 394 (1998); C. A. Doyle and S. P. Hunt, Neuroscience 89, 17 (1999).
27. We thank M. Schwei for technical assistance. Supported by National Institute on Drug Abuse grant 11986, National Institute of Neurological Disorders and Stroke grants 23970 and 31223, NIH Training grant DEO 7288, National Institute of Mental Health SBIR MH56368, a VA Merit Review, and the Spinal Cord Society.