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Substance P–Saporin for the Treatment of Intractable Pain

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Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Pain is a worldwide chronic health issue, and additional therapies are needed for the management of severe pain. Substance P–Saporin (SP-SAP) covalently links a biological toxin (SAP) and an endogenous peptide (SP) that targets that toxin to the subset of neurons expressing the NK1 receptor. SP-SAP, currently in phase I clinical trials, is unique as the only targeted toxin for pain to undergo human testing. We review the history of SP-SAP and related NK1-receptor targeted toxins. We review animal data on the safety and efficacy of SP-SAP for the treatment of pain in light of the results of NK1 receptor antagonists and knockouts/knockdowns of either SP or the NK1 receptor. Finally, we discuss possible mechanisms of action of SP-SAP.

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References

  • Abe T, Ohshita N, Sugiyo S, Moritani M, Kobayashi M, Takemura M (2005) Elimination of neurokinin-1 receptor neurons in caudal nucleus reverses the effects of systemic bicuculline on c-Fos expression in rat trigeminal sensory nucleus: I. High intensity electrical stimulation of the trigeminal ganglion. Neuroscience 133(3):739–747

    Article  CAS  PubMed  Google Scholar 

  • Agnati L, Fuxe K, Zoli M, Ozini I, Toffano G, Ferraguti F (1986) A correlation analysis of the regional distribution of central enkephalin and β-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128(2):201–207

    Article  CAS  PubMed  Google Scholar 

  • Allen JW, Mantyh PW, Horais K, Tozier N, Rogers SD, Ghilardi JR, Cizkova D, Grafe MR, Richter P, Lappi DA, Yaksh TL (2006) Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs. Toxicol Sci 91(1):286–298. doi:10.1093/toxsci/kfj143

    Article  CAS  PubMed  Google Scholar 

  • Auret K, Schug SA (2013) Pain management for the cancer patient – current practice and future developments. Best Pract Res Clin Anaesthesiol 27(4):545–561. doi:10.1016/j.bpa.2013.10.007

    Article  PubMed  Google Scholar 

  • Baker SJ, Morris JL, Gibbins IL (2003) Cloning of a C-terminally truncated NK-1 receptor from Guinea-pig nervous system. Brain Res Mol Brain Res 111(1–2):136–147

    Article  CAS  PubMed  Google Scholar 

  • Barthelemy I, Martineau D, Ong M, Matsunami R, Ling N, Benatti L, Cavallaro U, Soria M, Lappi DA (1993) The expression of saporin, a ribosome-inactivating protein from the plant Saponaria officinalis, in Escherichia coli. J Biol Chem 268(9):6541–6548

    CAS  PubMed  Google Scholar 

  • Beck AT, Ward C, Mendelson M (1961) Beck depression inventory (BDI). Arch Gen Psychiatry 4(6):561–571

    Article  CAS  PubMed  Google Scholar 

  • Benoliel R, Eliav E, Mannes AJ, Caudle RM, Leeman S, Iadarola MJ (1999) Actions of intrathecal diphtheria toxin-substance P fusion protein on models of persistent pain. Pain 79(2):243–253

    Article  CAS  PubMed  Google Scholar 

  • Beresford IJ, Birch PJ, Hagan RM, Ireland SJ (1991) Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345. Br J Pharmacol 104(2):292–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berridge KC (1989) Progressive degradation of serial grooming chains by descending decerebration. Behav Brain Res 33(3):241–253

    Article  CAS  PubMed  Google Scholar 

  • Brodin E, Linderoth B, Gazelius B, Ungerstedt U (1987) In vivo release of substance P in cat dorsal horn studied with microdialysis. Neurosci Lett 76(3):357–362

    Article  CAS  PubMed  Google Scholar 

  • Brown DC, Agnello K (2013) Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178–1185. doi:10.1097/ALN.0b013e3182a95188

    Article  CAS  PubMed  Google Scholar 

  • Brown JL, Liu H, Maggio JE, Vigna SR, Mantyh PW, Basbaum AI (1995) Morphological characterization of substance P receptor-immunoreactive neurons in the rat spinal cord and trigeminal nucleus caudalis. J Comp Neurol 356(3):327–344. doi:10.1002/cne.903560302

    Article  CAS  PubMed  Google Scholar 

  • Caberlotto L, Hurd YL, Murdock P, Wahlin JP, Melotto S, Corsi M, Carletti R (2003) Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. Eur J Neurosci 17(9):1736–1746

    Article  PubMed  Google Scholar 

  • Cao YQ, Mantyh PW, Carlson EJ, Gillespie A-M, Epstein CJ, Basbaum AI (1998) Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392(6674):390–394

    Article  CAS  PubMed  Google Scholar 

  • Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, Dale O, De Conno F, Fallon M, Hanna M, Haugen DF, Juhl G, King S, Klepstad P, Laugsand EA, Maltoni M, Mercadante S, Nabal M, Pigni A, Radbruch L, Reid C, Sjogren P, Stone PC, Tassinari D, Zeppetella G, European Palliative Care Research C, European Association for Palliative C (2012) Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 13(2):e58–e68. doi:10.1016/S1470-2045(12)70040-2

    Article  CAS  PubMed  Google Scholar 

  • Carlsson AM (1983) Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain 16(1):87–101

    Article  CAS  PubMed  Google Scholar 

  • Centers for Disease C, Prevention (2012) CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep 61(1):10–13

    Google Scholar 

  • Chang MM, Leeman SE, Niall HD (1971) Amino-acid sequence of substance P. Nat New Biol 232(29):86–87

    Article  CAS  PubMed  Google Scholar 

  • Choi J, Koehrn FJ, Sorkin LS (2012) Carrageenan induced phosphorylation of Akt is dependent on neurokinin-1 expressing neurons in the superficial dorsal horn. Mol Pain 8:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu LF, Liang DY, Li X, Sahbaie P, D’Arcy N, Liao G, Peltz G, David Clark J (2009) From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics. Pharmacogenet Genomics 19(3):193–205. doi:10.1097/FPC.0b013e328322e73d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuello AC, Jessell TM, Kanazawa I, Iversen LL (1977) Substance P: localization in synaptic vesicles in rat central nervous system. J Neurochem 29(4):747–751

    Article  CAS  PubMed  Google Scholar 

  • De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392(6674):394–397

    Article  CAS  PubMed  Google Scholar 

  • Dietl MM, Sanchez M, Probst A, Palacios JM (1989) Substance P receptors in the human spinal cord: decrease in amyotrophic lateral sclerosis. Brain Res 483(1):39–49

    Article  CAS  PubMed  Google Scholar 

  • Drapeau G, D'Orleans-Juste P, Dion S, Rhaleb N-E, Rouissi N-E, Regoli D (1987) Selective agonists for substance P and neurokinin receptors. Neuropeptides 10(1):43–54

    Article  CAS  PubMed  Google Scholar 

  • Duggan A, Morton C, Zhao Z, Hendry I (1987) Noxious heating of the skin releases immunoreactive substance P in the substantia gelatinosa of the cat: a study with antibody microprobes. Brain Res 403(2):345–349

    Article  CAS  PubMed  Google Scholar 

  • Duggan A, Hendry I, Morton C, Hutchinson W, Zhao Z (1988) Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat. Brain Res 451(1):261–273

    Article  CAS  PubMed  Google Scholar 

  • DuPen A, Shen D, Ersek M (2007) Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Manag Nurs 8(3):113–121

    Article  PubMed  Google Scholar 

  • Euler U, Gaddum J (1931) An unidentified depressor substance in certain tissue extracts. J Physiol 72(1):74

    Article  Google Scholar 

  • Fisher CE, Sutherland JA, Krause JE, Murphy JR, Leeman SE (1996) Genetic construction and properties of a diphtheria toxin-related substance P fusion protein: in vitro destruction of cells bearing substance P receptors. Proc Natl Acad Sci USA 93(14):7341–7345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garland AM, Grady EF, Payan DG, Vigna S, Bunnett N (1994) Agonist-induced internalization of the substance P (NK1) receptor expressed in epithelial cells. Biochem J 303:177–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillespie E, Leeman SE, Watts LA, Coukos JA, O’Brien MJ, Cerda SR, Farraye FA, Stucchi AF, Becker JM (2011) Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer. Proc Natl Acad Sci USA 108(42):17420–17425. doi:10.1073/pnas.1114275108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Go VL, Yaksh TL (1987) Release of substance P from the cat spinal cord. J Physiol 391:141–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, Bunnett NW (1995) Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor. Mol Biol Cell 6(5):509–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gureje O, Von Korff M, Simon GE, Gater R (1998) Persistent pain and well-being: a World Health Organization study in primary care. JAMA 280(2):147–151

    Article  CAS  PubMed  Google Scholar 

  • Hansen RN, Oster G, Edelsberg J, Woody GE, Sullivan SD (2011) Economic costs of nonmedical use of prescription opioids. Clin J Pain 27(3):194–202

    Article  PubMed  Google Scholar 

  • Hansen H, Noe CE, Racz GB (2014) The evolving role of opioid treatment in chronic pain management

    Google Scholar 

  • Henry J, Krnjević K, Morris M (1975) Substance P and spinal neurones. Can J Physiol Pharmacol 53(3):423–432

    Article  CAS  PubMed  Google Scholar 

  • Herrero JF, Laird JM, Lopez-Garcia JA (2000) Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 61(2):169–203

    Article  CAS  PubMed  Google Scholar 

  • Hill R (2000) NK1 (substance P) receptor antagonists – why are they not analgesic in humans? Trends Pharmacol Sci 21(7):244–246

    Article  CAS  PubMed  Google Scholar 

  • Hokfelt T, Kellerth JO, Nilsson G, Pernow B (1975a) Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res 100(2):235–252

    Article  CAS  PubMed  Google Scholar 

  • Hokfelt T, Kellerth JO, Nilsson G, Pernow B (1975b) Substance P: localization in the central nervous system and in some primary sensory neurons. Science 190(4217):889–890

    Article  CAS  PubMed  Google Scholar 

  • Hu HZ, Li ZW, Si JQ (1997) Evidence for the existence of substance P autoreceptor in the membrane of rat dorsal root ganglion neurons. Neuroscience 77(2):535–541

    Article  CAS  PubMed  Google Scholar 

  • Hui SC, Sevilla EL, Ogle CW (1996) Prevention by the 5-HT3 receptor antagonist, ondansetron, of morphine-dependence and tolerance in the rat. Br J Pharmacol 118(4):1044–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hylden JL, Wilcox GL (1981) Intrathecal substance P elicits a caudally-directed biting and scratching behavior in mice. Brain Res 217(1):212–215

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299(5610):1237–1240. doi:10.1126/science.1080659

    Article  CAS  PubMed  Google Scholar 

  • Kage R, Leeman SE, Boyd ND (1993) Biochemical characterization of two different forms of the substance P receptor in rat submaxillary gland. J Neurochem 60(1):347–351

    Article  CAS  PubMed  Google Scholar 

  • Kandel ER, Schwartz JH, Jessell TM (2000) Principles of neural science, vol 4. McGraw-Hill, New York

    Google Scholar 

  • Khasabov SG, Simone DA (2013) Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. Neuroscience 250:151–165. doi:10.1016/j.neuroscience.2013.06.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci Off J Soc Neurosci 22(20):9086–9098

    CAS  Google Scholar 

  • Khasabov SG, Brink TS, Schupp M, Noack J, Simone DA (2012) Changes in response properties of rostral ventromedial medulla neurons during prolonged inflammation: modulation by neurokinin-1 receptors. Neuroscience 224:235–248. doi:10.1016/j.neuroscience.2012.08.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King T, Gardell LR, Wang R, Vardanyan A, Ossipov MH, Malan TP Jr, Vanderah TW, Hunt SP, Hruby VJ, Lai J, Porreca F (2005) Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain 116(3):276–288. doi:10.1016/j.pain.2005.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein CM, Coggeshall RE, Carlton SM, Sorkin LS (1992) The effects of A- and C-fiber stimulation on patterns of neuropeptide immunostaining in the rat superficial dorsal horn. Brain Res 580(1):121–128

    Article  CAS  PubMed  Google Scholar 

  • Kuraishi Y, Hirota N, Sato Y, Hino Y, Satoh M, Takagi H (1985) Evidence that substance P and somatostatin transmit separate information related to pain in the spinal dorsal horn. Brain Res 325(1):294–298

    Article  CAS  PubMed  Google Scholar 

  • Lai JP, Ho WZ, Kilpatrick LE, Wang X, Tuluc F, Korchak HM, Douglas SD (2006) Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation. Proc Natl Acad Sci USA 103(20):7771–7776. doi:10.1073/pnas.0602563103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai JP, Cnaan A, Zhao H, Douglas SD (2008) Detection of full-length and truncated neurokinin-1 receptor mRNA expression in human brain regions. J Neurosci Methods 168(1):127–133. doi:10.1016/j.jneumeth.2007.10.004

    Article  CAS  PubMed  Google Scholar 

  • Lappi DA, Wiley RG (2000) Substance P-Saporin (SP-SAP) conjugates and methods of use thereof. Google Patents

    Google Scholar 

  • Larsen PJ, Mikkelsen JD, Mau S, Særmark T (1989) Binding and internalization of a iodinated substance P analog by cultured anterior pituitary cells. Mol Cell Endocrinol 65(1):91–101

    Article  CAS  PubMed  Google Scholar 

  • Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53(4):597–652

    CAS  PubMed  Google Scholar 

  • Lee Y, Song J (1991) A study of the reliability and the validity of the BDI, SDS, and MMPI-D scales. Korean J Clin Psychol 10(1):98–113

    Google Scholar 

  • Leffler A, Ahlstedt I, Engberg S, Svensson A, Billger M, Oberg L, Bjursell MK, Lindstrom E, von Mentzer B (2009) Characterization of species-related differences in the pharmacology of tachykinin NK receptors 1, 2 and 3. Biochem Pharmacol 77(9):1522–1530. doi:10.1016/j.bcp.2009.01.020

    Article  CAS  PubMed  Google Scholar 

  • Lembeck F (1953) Central transmission of afferent impulses. III. Incidence and significance of the substance P in the dorsal roots of the spinal cord. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 219(3):197–213

    Article  CAS  PubMed  Google Scholar 

  • Liang DY, Li X, Clark JD (2011) 5-Hydroxytryptamine type 3 receptor modulates opioid-induced hyperalgesia and tolerance in mice. Anesthesiology 114(5):1180–1189. doi:10.1097/ALN.0b013e31820efb19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantyh PW, Hunt SP (1985) The autoradiographic localization of substance P receptors in the rat and bovine spinal cord and the rat and cat spinal trigeminal nucleus pars caudalis and the effects of neonatal capsaicin. Brain Res 332(2):315–324

    Article  CAS  PubMed  Google Scholar 

  • Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE (1995a) Rapid endocytosis of a G protein-coupled receptor: substance P evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci USA 92(7):2622–2626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE et al (1995b) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268(5217):1629–1632

    Article  CAS  PubMed  Google Scholar 

  • Mantyh PW, Rogers SD, Ghilardi JR, Maggio JE, Mantyh CR, Vigna SR (1996) Differential expression of two isoforms of the neurokinin-1 (substance P) receptor in vivo. Brain Res 719(1–2):8–13

    Article  CAS  PubMed  Google Scholar 

  • Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, Simone DA (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278(5336):275–279

    Article  CAS  PubMed  Google Scholar 

  • Marshall G, Shehab S, Spike R, Todd A (1996) Neurokinin-1 receptors on lumbar spinothalamic neurons in the rat. Neuroscience 72(1):255–263

    Article  CAS  PubMed  Google Scholar 

  • Masu Y, Nakayama K, Tamaki H, Harada Y, Kuno M, Nakanishi S (1987) cDNA eloping of bovine substance-K receptor through oocyte expression system. Nature 329:836–838

    Article  CAS  PubMed  Google Scholar 

  • Matsumura H, Sakurada T, Hara A, Sakurada S, Kisara K (1985) Characterization of the hyperalgesic effect induced by intrathecal injection of substance P. Neuropharmacology 24(5):421–426

    Article  CAS  PubMed  Google Scholar 

  • McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, Lau J, Carr D (2003) Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 4(5):231–256

    Article  PubMed  Google Scholar 

  • Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA, Grond S (2001) Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93(3):247–257

    Article  CAS  PubMed  Google Scholar 

  • Mustafa G, Anderson EM, Bokrand-Donatelli Y, Neubert JK, Caudle RM (2013) Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A. Pain 154(11):2547–2553

    Article  CAS  PubMed  Google Scholar 

  • Naono-Nakayama R, Sunakawa N, Ikeda T, Nishimori T (2011) Knockdown of the tachykinin neurokinin 1 receptor by intrathecal administration of small interfering RNA in rats. Eur J Pharmacol 670(2–3):448–457. doi:10.1016/j.ejphar.2011.09.035

    Article  CAS  PubMed  Google Scholar 

  • Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, Mantyh PW (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286(5444):1558–1561

    Article  CAS  PubMed  Google Scholar 

  • Ninkovic M, Beaujouan J, Torrens Y, Saffroy M, Hall M, Glowinski J (1984) Differential localization of tachykinin receptors in rat spinal cord. Eur J Pharmacol 106(2):463–464

    Article  CAS  PubMed  Google Scholar 

  • Oppe M, Devlin NJ, Szende A (2007) EQ-5D value sets: inventory, comparative review and user guide

    Google Scholar 

  • Organization WH (1986) Cancer pain relief World Health Organization. Geneva, Switzerland

    Google Scholar 

  • Organization WH (1996) Cancer pain relief: with a guide to opioid availability. World Health Organization

    Google Scholar 

  • Patrick DL, Deyo RA, Atlas SJ, Singer DE, Chapin A, Keller RB (1995) Assessing health-related quality of life in patients with sciatica. Spine 20(17):1899–1908

    Article  CAS  PubMed  Google Scholar 

  • Pernow B (1953) Studies on substance P; purification, occurrence and biological actions. Acta Physiol Scand Suppl 29(105):1–89

    CAS  PubMed  Google Scholar 

  • Piercey MF, Dobry PJ, Schroeder LA, Einspahr FJ (1981) Behavioral evidence that substance P may be a spinal cord sensory neurotransmitter. Brain Res 210(1):407–412

    Article  CAS  PubMed  Google Scholar 

  • Polgar E, Durrieux C, Hughes DI, Todd AJ (2013) A quantitative study of inhibitory interneurons in laminae I–III of the mouse spinal dorsal horn. PLoS One 8(10):e78309. doi:10.1371/journal.pone.0078309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quirion R, Shults CW, Moody TW, Pert CB, Chase TN, O’Donohue TL (1983) Autoradiographic distribution of substance P receptors in rat central nervous system. Nature 303(5919):714–716

    Article  CAS  PubMed  Google Scholar 

  • Rabin R, Charro F (2001) EQ-SD: a measure of health status from the EuroQol Group. Ann Med 33(5):337–343

    Article  CAS  PubMed  Google Scholar 

  • Rahman W, Suzuki R, Hunt SP, Dickenson AH (2008) Selective ablation of dorsal horn NK1 expressing cells reveals a modulation of spinal alpha2-adrenergic inhibition of dorsal horn neurones. Neuropharmacology 54(8):1208–1214. doi:10.1016/j.neuropharm.2008.03.014

    Article  CAS  PubMed  Google Scholar 

  • Rainsford K (1999) Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 107(6):27–35

    Article  Google Scholar 

  • Randić M, Miletić V (1977) Effect of substance P in cat dorsal horn neurones activated by noxious stimuli. Brain Res 128(1):164–169

    Article  PubMed  Google Scholar 

  • Rexed B (1952) The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol 96(3):414–495

    Article  CAS  PubMed  Google Scholar 

  • Rexed B (1954) A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 100(2):297–379

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro-da-Silva A, Hökfelt T (2000) Neuroanatomical localisation of substance P in the CNS and sensory neurons. Neuropeptides 34(5):256–271

    Article  CAS  PubMed  Google Scholar 

  • Ripamonti CI, Santini D, Maranzano E, Berti M, Roila F, Group EGW (2012) Management of cancer pain: ESMO clinical practice guidelines. Ann Oncol 23(Suppl 7):vii139–vii154. doi:10.1093/annonc/mds233

    Article  PubMed  Google Scholar 

  • Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2009) Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain. Eur J Neurosci 29(4):727–737. doi:10.1111/j.1460-9568.2009.06616.x

    Article  PubMed  Google Scholar 

  • Roland M, Morris R (1983) A study of the natural history of back pain: part I: development of a reliable and sensitive measure of disability in low-back pain. Spine 8(2):141–144

    Article  CAS  PubMed  Google Scholar 

  • Rygh LJ, Suzuki R, Rahman W, Wong Y, Vonsy JL, Sandhu H, Webber M, Hunt S, Dickenson AH (2006) Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Eur J Neurosci 24(3):761–772. doi:10.1111/j.1460-9568.2006.04968.x

    Article  PubMed  Google Scholar 

  • Sahbaie P, Shi X, Li X, Liang D, Guo TZ, Qiao Y, Yeomans DC, Kingery WS, David Clark J (2012) Preprotachykinin-A gene disruption attenuates nociceptive sensitivity after opioid administration and incision by peripheral and spinal mechanisms in mice. J Pain 13(10):997–1007. doi:10.1016/j.jpain.2012.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saka E, Iadarola M, Fitzgerald DJ, Graybiel AM (2002) Local circuit neurons in the striatum regulate neural and behavioral responses to dopaminergic stimulation. Proc Natl Acad Sci USA 99(13):9004–9009. doi:10.1073/pnas.132212499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakurada T, Yogo H, Tan-No K, Sakurada S, Kisara K (1994) Behavioral activation of neurokinin-1 agonists in relation to enzymatic degradation in the spinal cord. J Pharm Sci 83(1):2–4

    Article  CAS  PubMed  Google Scholar 

  • Santarelli L, Gobbi G, Debs PC, Sibille EL, Blier P, Hen R, Heath MJ (2001) Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci USA 98(4):1912–1917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaffalitzky De Muckadell OB, Aggestrup S, Stentoft P (1986) Flushing and plasma substance P concentration during infusion of synthetic substance P in normal man. Scand J Gastroenterol 21(4):498–502

    Article  CAS  PubMed  Google Scholar 

  • Schug SA, Zech D, Dörr U (1990) Cancer pain management according to WHO analgesic guidelines. J Pain Symptom Manag 5(1):27–32

    Article  CAS  Google Scholar 

  • Scott J, Huskisson E (1976) Graphic representation of pain. Pain 2(2):175–184

    Article  CAS  PubMed  Google Scholar 

  • Shigemoto R, Yokota Y, Tsuchida K, Nakanishi S (1990) Cloning and expression of a rat neuromedin K receptor cDNA. J Biol Chem 265(2):623–628

    CAS  PubMed  Google Scholar 

  • Shults CW, Quirion R, Chronwall B, Chase TN, O’Donohue TL (1984) A comparison of the anatomical distribution of substance P and substance P receptors in the rat central nervous system. Peptides 5(6):1097–1128

    Article  CAS  PubMed  Google Scholar 

  • Simons CT, Gogineni AG, Iodi Carstens M, Carstens E (2002) Reduced aversion to oral capsaicin following neurotoxic destruction of superficial medullary neurons expressing NK-1 receptors. Brain Res 945(1):139–143

    Article  CAS  PubMed  Google Scholar 

  • Sindrup SH, Jensen TS (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83(3):389–400

    Article  CAS  PubMed  Google Scholar 

  • Sjodin L (1992) Cholecystokinin-induced inhibition of endocytosis of receptor-bound substance P in pancreatic acinar cells. J Recept Res 12(3):323–350

    Article  CAS  PubMed  Google Scholar 

  • Snijdelaar DG, Dirksen R, Slappendel R, Crul BJ (2000) Substance P. Eur J Pain 4(2):121–135. doi:10.1053/eujp.2000.0171

    Article  CAS  PubMed  Google Scholar 

  • Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW (2014) Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev 94(1):265–301. doi:10.1152/physrev.00031.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stirpe F (2004) Ribosome-inactivating proteins. Toxicon 44(4):371–383. doi:10.1016/j.toxicon.2004.05.004

    Article  CAS  PubMed  Google Scholar 

  • Stirpe F, Gasperi-Campani A, Barbieri L, Falasca A, Abbondanza A, Stevens W (1983) Ribosome-inactivating proteins from the seeds of Saponaria officinalis L. (soapwort), of Agrostemma githago L. (corn cockle) and of Asparagus officinalis L. (asparagus), and from the latex of Hura crepitans L. (sandbox tree). Biochem J 216:617–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH (2002) Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci 5(12):1319–1326. doi:10.1038/nn966

    Article  CAS  PubMed  Google Scholar 

  • Takahashi T, Otsuka M (1975) Regional distribution of substance P in the spinal cord and nerve roots of the cat and the effect of dorsal root section. Brain Res 87(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Takano M, Takano Y, Yaksh TL (1993) Release of calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal polypeptide (VIP) from rat spinal cord: modulation by α2 agonists. Peptides 14(2):371–378

    Article  CAS  PubMed  Google Scholar 

  • Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11(12):823–836. doi:10.1038/nrn2947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todd AJ, Spike RC, Polgar E (1998) A quantitative study of neurons which express neurokinin-1 or somatostatin sst2a receptor in rat spinal dorsal horn. Neuroscience 85(2):459–473

    Article  CAS  PubMed  Google Scholar 

  • Todd AJ, McGill MM, Shehab SAS (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur J Neurosci 12(2):689–700. doi:10.1046/j.1460-9568.2000.00950.x

    Article  CAS  PubMed  Google Scholar 

  • Torrens Y, Beaujouan JC, Viger A, Glowinski J (1983) Properties of a 125I-substance P derivative binding to synaptosomes from various brain structures and the spinal cord of the rat. Naunyn Schmiedeberg’s Arch Pharmacol 324(2):134–139

    Article  CAS  Google Scholar 

  • Tousignant C, Guillemette G, Drapeau G, Regoli D (1989) Comparison of binding assay and biological activity on a NK-1 system with new selective agonists. Neuropeptides 14(4):275–283

    Article  CAS  PubMed  Google Scholar 

  • Tousignant C, Guillemette G, Drapeau G, Dion S, Regoli D (1990) 125I-BH [Sar9, Met (O2)11]-SP, a new selective ligand for the NK-1 receptor in the central nervous system. Brain Res 524(2):263–270

    Article  CAS  PubMed  Google Scholar 

  • Turk DC, Wilson HD, Cahana A (2011) Treatment of chronic non-cancer pain. Lancet 377(9784):2226–2235. doi:10.1016/S0140-6736(11)60402-9

    Article  CAS  PubMed  Google Scholar 

  • van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J (2007) Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18(9):1437–1449. doi:10.1093/annonc/mdm056

    Article  PubMed  Google Scholar 

  • Vera-Portocarrero LP, Zhang ET, King T, Ossipov MH, Vanderah TW, Lai J, Porreca F (2007) Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways. Pain 129(1–2):35–45. doi:10.1016/j.pain.2006.09.033

    Article  CAS  PubMed  Google Scholar 

  • Vierck CJ Jr, Kline RH, Wiley RG (2003) Intrathecal substance P-saporin attenuates operant escape from nociceptive thermal stimuli. Neuroscience 119(1):223–232

    Article  CAS  PubMed  Google Scholar 

  • Viger A, Beaujouan J, Torrens Y, Glowinski J (1983) Specific binding of a 125I-substance P derivative to rat brain synaptosomes. J Neurochem 40(4):1030–1039

    Article  CAS  PubMed  Google Scholar 

  • von Euler U (1936) Untersuchungen über Substanz P, die atropinfeste, darmerregende und gefäßerweiternde Substanz aus Darm und Hirn. Naunyn Schmiedeberg’s Arch Pharmacol 181(2):181–197

    Article  Google Scholar 

  • Wang X, Marvizon JC (2002) Time-course of the internalization and recycling of neurokinin 1 receptors in rat dorsal horn neurons. Brain Res 944(1–2):239–247

    Article  CAS  PubMed  Google Scholar 

  • Weisshaar CL, Winkelstein BA (2014) Ablating spinal NK1-bearing neurons eliminates the development of pain and reduces spinal neuronal hyperexcitability and inflammation from mechanical joint injury in the rat. J Pain 15(4):378–386. doi:10.1016/j.jpain.2013.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiese AJ, Rathbun M, Butt MT, Malkmus SA, Richter PJ, Osborn KG, Xu Q, Veesart SL, Steinauer JJ, Higgins D, Lappi DA, Russell B, Yaksh TL (2013) Intrathecal substance P-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163–1177. doi:10.1097/ALN.0b013e3182a95164

    Article  CAS  PubMed  Google Scholar 

  • Wiley RG, Lappi DA (1997) Destruction of neurokinin-1 receptor expressing cells in vitro and in vivo using substance P-saporin in rats. Neurosci Lett 230(2):97–100

    Article  CAS  PubMed  Google Scholar 

  • Wiley RG, Lappi DA (1999) Targeting neurokinin-1 receptor-expressing neurons with [Sar9,Met(O2)11] substance P-saporin. Neurosci Lett 277(1):1–4

    Article  CAS  PubMed  Google Scholar 

  • Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043–1054

    Article  CAS  PubMed  Google Scholar 

  • Wiley RG, Kline RH, Vierck CJ Jr (2007) Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: behavioral and anatomical analyses. Neuroscience 146(3):1333–1345. doi:10.1016/j.neuroscience.2007.01.066

    Article  CAS  PubMed  Google Scholar 

  • Woolf CJ (1984) Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain 18(4):325–343

    Article  CAS  PubMed  Google Scholar 

  • Yaksh T, Jessell TM, Gamse R, Mudge A, Leeman SE (1980) Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 286:155–157

    Article  CAS  PubMed  Google Scholar 

  • Yashpal K, Dam TV, Quirion R (1990) Quantitative autoradiographic distribution of multiple neurokinin binding sites in rat spinal cord. Brain Res 506(2):259–266

    Article  CAS  PubMed  Google Scholar 

  • Yezierski RP (2006) Chapter 21 pain following spinal cord injury: central mechanisms. Handb Clin Neurol 81:293–29V. doi:10.1016/S0072-9752(06)80025-4

    Article  PubMed  Google Scholar 

  • Yezierski RP, Yu CG, Mantyh PW, Vierck CJ, Lappi DA (2004) Spinal neurons involved in the generation of at-level pain following spinal injury in the rat. Neurosci Lett 361(1–3):232–236. doi:10.1016/j.neulet.2003.12.035

    Article  CAS  PubMed  Google Scholar 

  • Yokota Y, Sasai Y, Tanaka K, Fujiwara T, Tsuchida K, Shigemoto R, Kakizuka A, Ohkubo H, Nakanishi S (1989) Molecular characterization of a functional cDNA for rat substance P receptor. J Biol Chem 264(30):17649–17652

    CAS  PubMed  Google Scholar 

  • Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA (1995) Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 63(1):65–76

    Article  CAS  PubMed  Google Scholar 

  • Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, König M, Palkovits M, Mezey É (1998) Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA 95(5):2630–2635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors would like to thank the University of Texas Southwestern Medical Center for financial support. Hugh Nymeyer would like to thank Tracy Nymeyer for her personal and financial support.

Declaration of Conflicting Interests

Douglas Lappi and Dennis Higgins are officers of Advanced Targeting Systems, which manufactures SP-SAP.

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Authors and Affiliations

  1. Hematology/Oncology Division, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX, 75390-8852, USA

    Hugh Nymeyer & Arthur E. Frankel

  2. Advanced Targeting Systems, 10451 Roselle St., #300, San Diego, CA, 92121, USA

    Douglas A. Lappi & Denise Higgins

  3. Department of Anesthesiology & Pain Management, UT Southwestern Medical Center, Dallas, TX, 75235-9068, USA

    Carl E. Noe

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  1. Hugh Nymeyer
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  2. Douglas A. Lappi
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  3. Denise Higgins
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  4. Carl E. Noe
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  5. Arthur E. Frankel
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Correspondence to Arthur E. Frankel .

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  1. NBE-Therapeutics Ltd., Basel, Switzerland

    Ulf Grawunder

  2. Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Stefan Barth

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Nymeyer, H., Lappi, D.A., Higgins, D., Noe, C.E., Frankel, A.E. (2017). Substance P–Saporin for the Treatment of Intractable Pain. In: Grawunder, U., Barth, S. (eds) Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins. Milestones in Drug Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-46877-8_6

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