Tachykinins pp 441-457 | Cite as
Substance P (NK1) Receptor Antagonists—Analgesics or Not?
Abstract
Over the last two decades much research has focused on the role of substance P in pain and on the development of substance P antagonists as novel analgesics. Despite the identification of high affinity and selective substance P (NK1) receptor antagonists and a plethora of preclinical data supporting an analgesic profile of these agents, the outcome from clinical trials has been extremely disappointing with no clear analgesic efficacy being observed in a variety of pain states. This has led the pain community to seriously question the predictability and utility of preclinical pain assays, especially for novel targets. This chapter will review the animal studies and clinical trials with NK1 receptor antagonists and suggests possible reason s for the apparent mismatch between preclinical and clinical studies in pain.
Keywords
Pain Hyperalgesia Behaviour StressPreview
Unable to display preview. Download preview PDF.
References
- Ardid D, Guilbaud G (1992) Antinociceptive effects of acute and ‘chronic’ injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats. Pain 49: 279–287PubMedCrossRefGoogle Scholar
- Awawdeh L, Lundy FT, Shaw C, Lamey PJ, Linden GJ, Kennedy JG (2002) Quantitative analysis of substance P, neurokinin A and calcitonin gene-related peptide in pulp tissue from painful and healthy human teeth. Int Endod J 35: 30–36PubMedCrossRefGoogle Scholar
- Beresford FT, 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: 292–293PubMedCrossRefGoogle Scholar
- Binder W, Scott C, Walker JS (1999) Involvement of substance P in the anti-inflammatory effects of the peripherally selective kappa-opioid asimadoline and the NK1 antagonist GR 205171. Eur J Neurosci 11: 2065–2072PubMedCrossRefGoogle Scholar
- Block GA, Rue D, Panebianco D et al. (1998) The substance P receptor antagonist L-754,030 (MK-0869) is ineffective in he treatment of post herpetic neuralgia. Neurology 4: A225Google Scholar
- Boyce S, Hill RG (2000) Discrepant results from preclinical and clinical studies on the potential of substance P-receptor antagonists compounds as analgesics. In Devor M et al (eds) Proceedings of the 9th World Congress on Pain. IASP press, Seattle, pp 313–324Google Scholar
- Boyce S, Laird JMA, Tattersall FD et al (1993) Antinociceptive effects of NK1 receptor antagonists: comparison of behavioural and electrophysiological tests. 7th World Congress on Pain, abstract 641Google Scholar
- Brain SD, Poyner DR, Hill RG (2002) CGRP receptors: a headache to study, but will antagonists prove therapeutic in migraine? Trends Pharmacol Sci 23: 51–53PubMedCrossRefGoogle Scholar
- Cascieri MA, Ber E, Fong TM, Sadowski S, Bansal A, Swain C, Seward E, Frances B, Burns D, Strader CD (1992) Characterization of the binding of a potent, selective, radioiodinated antagonist to the human neurokinin-1 receptor. Mol PharmacoI 42: 458–463Google Scholar
- Clouse RE (1994) Antidepressants for functional gastrointestinal syndromes. Dig Dis Sci 39: 2352–2363PubMedCrossRefGoogle Scholar
- Connor HE, Bertin L, Gillies et al. (1998) Clinical evaluation of a novel, potent, CNS penetrating NK receptor antagonist in the acute treatment of migraine. Cephalalgia 18: 392Google Scholar
- Coudore-Civiale M, Courteix C, Boucher M, Fialip J, Eschalier A (2000) Evidence for an involvement of tachykinins in allodynia in streptozocin-induced diabetic rats. Eur J Pharmacol 401: 47–53PubMedCrossRefGoogle Scholar
- Cridland RA, Henry JL (1986) Comparison of the effects of substance P, neurokinin A, physalaemin and eledoisin in facilitating a nociceptive reflex in the rat. Brain Res 381: 93–99PubMedCrossRefGoogle Scholar
- Cumberbatch MJ, Carlson E, Wyatt A, Boyce S, Hill RG, Rupniak NM (1998) Reversal of behavioural and electrophysiological correlates of experimental peripheral neuropathy by the NK1 receptor antagonist GR205171 in rats. NeuropharmacoI 37: 1535–1543.CrossRefGoogle Scholar
- Daemen MA, Kurvers HA, Kitslaar PJ, Slaaf DW, Bullens PH, Van den Wildenberg FA (1998) Neurogenic inflammation in an animal model of neuropathic pain. Neurol Res 20: 41–45PubMedGoogle 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: 394–397PubMedCrossRefGoogle Scholar
- Dionne RA (1999) Clinical analgesic trials of NK1 antagonists. Curr Opin CPNS Invest Drugs 1: 82–85Google Scholar
- Dionne RA, Max MB, Gordon SM, Parada S, Sang C, Gracely RH, Sethna NF, MacLean DB (1998) The substance P receptor antagonist CP-99,994 reduces acute postoperative pain. Clin Pharmacol Ther 64: 562–568PubMedCrossRefGoogle Scholar
- Drossman DA (1999) Do psychosocial factors define symptom severity and patient status in irritable bowel syndrome? Am J Med 107: 41S–50SPubMedCrossRefGoogle Scholar
- Duggan AW, Morton CR, Zhao ZQ, Hendry IA (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: 345–349PubMedCrossRefGoogle Scholar
- Edvinsson L (2001) Calcitonin gene-related peptide (CGRP) and the pathophysiology of headache: therapeutic implications. CNS Drugs 15: 745–753PubMedCrossRefGoogle Scholar
- Field MJ, McCleary S, Boden P, Suman-Chauhan N, Hughes J, Singh L (1998) Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat. J Pharmacol Exp Ther 285: 1226–1232PubMedGoogle Scholar
- Field MJ, Gonzalez MI, Tallarida RJ, Singh L (2002) Gabapentin and the neurokinin1, receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain. J Pharmacol Exp Ther 303: 730–735PubMedCrossRefGoogle Scholar
- Garret C, Carruette A, Fardin V, Moussaoui S, Peyronel JF, Blanchard JC, Laduron PM (1992) RP 67580, a potent and selective substance P non-peptide antagonist. C R Acad Sci III 314: 199–204PubMedGoogle Scholar
- Gallai V, Sarchielli P, Floridi A, Franceschini M, Codini M, Glioti G, Trequattrini A, Palumbo R (1995) Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15: 384–390PubMedGoogle Scholar
- Gesztesi ZS, Song D, White PF (1998) Comparison of a new NK-1 antagonist (CP122,721) to ondansetron in the prevention of postoperative nausea and vomiting. Anesth Analg 86: S32CrossRefGoogle Scholar
- Goldstein DJ, Offen WW, Klein EG (1999) Lanepitant, a NK1 antagonist, in migraine prophylaxis. Clin Pharmacol Therap 65: AbstractGoogle Scholar
- Goldstein DJ, Wang 0 (1999) Lanepitant, a NK1 antagonist, in painful diabetic neuropathy. Clin Pharmacol Therap 65:AbstractGoogle Scholar
- Goldstein DJ, Wang 0, Saper JR, Stoltz R, Silberstein SD, Mathew NT (1997) Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17: 785–790PubMedCrossRefGoogle Scholar
- Goldstein DJ, Wang 0, Todd TE (1998) Lanepitant in osteoarthritis pain. Clin Pharmacol Ther 63: 168Google Scholar
- Gonzalez MI, Field MJ, Hughes J, Singh L (2000) Evaluation of selective NK1 receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 294: 444–450PubMedGoogle Scholar
- Goto T, Tanaka T (2002) TAchykinins and tachykinin receptors in bone. Microscopy Res and Technique 58: 91–97CrossRefGoogle Scholar
- Hargreaves R (2002) Imaging substance Preceptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 63 Suppl: 18–24PubMedGoogle Scholar
- Headley PM, Livingston A (1989) Pain and stress in animals: problems of assessment and treatment. Front Pain 1: 1–4Google Scholar
- Henry JL (1976) Effects of substance P on functionally identified units in cat spinal cord. Brain Res 114: 439–451PubMedCrossRefGoogle Scholar
- Hill RG, Rupniak NMJ (1999) Tachykinin receptors and the potential of tachykinin antagonists as clinically effective analgesics and anti-inflammatory agents. In Brain SB and Moore PK (eds) Pain and neurogenic inflammation. Birkhäuser, Basel, pp 313–333CrossRefGoogle Scholar
- Honore P, Mantyh P (2000) Bone cancer pain: from mechanism to model to therapy. Pain Med 1: 303–309PubMedCrossRefGoogle Scholar
- Iyengar S, Hipskind PA, Gehlert DR, Schober D, Lobb KL, Nixon JA, Helton DR, Kallman MJ, Boucher S, Couture R, Li DL, Simmons RM (1997) LY303870, a centrally active neurokinin-1 antagonist with a long duration of action. J Pharmacol Exp Ther 280: 774–785PubMedGoogle Scholar
- Juranek I, Lembeck F (1997) Afferent C-fibres release substance P and glutamate. Can J Physiol Pharmacol 75: 661–664PubMedCrossRefGoogle Scholar
- Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Rupniak NM (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281: 1640–1645PubMedCrossRefGoogle Scholar
- Laird JM, Hargreaves RJ, Hill RG (1993) Effect of RP 67580, a non-peptide neurokinin, receptor antagonist, on facilitation of a nociceptive spinal flexion reflex in the rat. Br J PharmacoI 109: 713–718CrossRefGoogle Scholar
- Laird JM, Olivar T, Roza C, De Felipe C, Hunt SP, Cervero F (2000) Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98: 345–352PubMedCrossRefGoogle Scholar
- Laird JM, Roza C, De Felipe C, Hunt SP, Cervero F (2001) Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice. Pain 90: 97–103PubMedCrossRefGoogle Scholar
- Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may playa causative role in migraine. Cephalalgia 22: 54–61PubMedCrossRefGoogle Scholar
- Li JL, Ding YQ, Xiong KH, Li JS, Shigemoto R, Mizuno N (1998) Substance Preceptor (NK1)-immunoreactive neurons projecting to the periaqueductal gray: distribution in the spinal trigeminal nucleus and the spinal cord of the rat. Neurosci Res 30: 219–225PubMedCrossRefGoogle Scholar
- Littman B, Newton FA, Russell IJ (1999) Substance P antagonism in fibromyalgia: a trial with CJ-11,974. Proceedings of the 9th World Congress on Pain. IASP Press, Seattle, p67Google Scholar
- Mansikka H, Sheth RN, DeVries C, Lee H, Winchurch R, Raja SN (2000) Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in neurokinin-1 receptor knockout mice. Exp Neurol 162: 343–349PubMedCrossRefGoogle Scholar
- Mansikka H, Shiotani M, Winchurch R, Raja SN (1999) Neurokinin-1 receptors are involved in behavioral responses to high-intensity heat stimuli and capsaicin-induced hyperalgesia in mice. Anesthesiology 90: 1643–1649PubMedCrossRefGoogle Scholar
- Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE, Simone DA (1995) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268: 1629–1632PubMedCrossRefGoogle Scholar
- Mantyh PW, Hunt SP (1985) The autoradiographic localization of substance Preceptors 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: 315–324PubMedCrossRefGoogle 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: 275–279PubMedCrossRefGoogle Scholar
- Martinez-Caro L, Laird JM (2000) Allodynia and hyperalgesia evoked by sciatic mono-neuropathy in NK1 receptor knockout mice. Neuroreport 11: 1213–1217PubMedCrossRefGoogle Scholar
- Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH (1988) Association of pain relief with drug side-effects in postherpetic neuralgia: a single-dose study clonidine, codeine, ibuprofen and placebo. Clin Pharmacol Ther 43: 363–371PubMedCrossRefGoogle Scholar
- McLean S, Ganong AH, Seeger TF, Bryce DK, Pratt KG, Reynolds LS, Siok CJ, Lowe JA 3rd, Heym J (1991) Activity and distribution of binding sites in brain of a nonpeptide substance P (NK1) receptor antagonist. Science 251: 437–439PubMedCrossRefGoogle Scholar
- Molander C, Ygge J, Dalsgaard CJ (1987) Substance P-, somatostatin-and calcitonin gene-related peptide-like immunoreactivity and fluoride resistant acid phosphatase-activity in relation to retrogradely labeled cutaneous, muscular and visceral primary sensory neurons in the rat. Neurosci Lett 74: 37–42PubMedCrossRefGoogle Scholar
- Nagy JI, Hunt SP, Iversen LL, Emson PC (1981) Biochemical and anatomical observations on the degeneration of peptide-containing primary afferent neurons after neonatal capsaicin. Neuroscience 6: 1923–1934PubMedCrossRefGoogle Scholar
- Natsugari H, Ikeura Y, Kiyota Y, Ishichi Y, Ishimaru T, Saga 0, Shirafuji H, Tanaka T, Kamo I, Doi T et al (1995) Novel, potent, and orally active substance P antagonists: synthesis and antagonist activity of N-benzylcarboxamide derivatives of pyrido[3,4b] pyridine. J Med Chem 38: 3106–3120PubMedCrossRefGoogle Scholar
- Navari RM, Reinhardt RR, Gralla RJ, Kris MG, Hesketh PJ, Khojasteh A, Kindler H, Grote TH, Pendergrass K, Grunberg SM, Carides AD, Gertz BJ (1999) Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group. N Engl J Med 340: 190–195PubMedCrossRefGoogle Scholar
- Neckers LM, Schwartz JP, Wyatt RJ, Speciale SG (1979) Substance P afferents from the ha-benula innervate the dorsal raphe nucleus. Exp Brain Res 37: 619–23PubMedCrossRefGoogle Scholar
- Norman B, Panebianco D, Block GA (1998) A controlled, in clinic study to explore the preliminary safety and efficacy of intravenous L-758,298 (a prodrug of the NK1 receptor antagonist L-754,030) in the acute treatment of migraine. Cephalalgia 18: 4507–442Google Scholar
- Okano S, Ikeura Y, Inatomi N (2002) Effects of tachykinin NK1 receptor antagonists on the viscerosensory response caused by colorectal distention in rabbits. J Pharmacol Exp Ther 300: 925–931PubMedCrossRefGoogle Scholar
- Okayama Y, Ono Y, Nakazawa T, Church MK, Mori M (1998) Human skin mast cells pro duce TNF-alpha by substance P. Int Arch Allergy Immunol 117 Suppll: 48–51PubMedCrossRefGoogle Scholar
- Patel S, Gentry CT, Campbell EA (1996) A model for in vivo evaluation of tachykinin NK1 receptor antagonists using carrageenan-induced hyperalgesia in the guinea pig paw. Br J Pharmacol 117: 248PGoogle Scholar
- Phebus LA, Johnson KW, Stengel PW, Lobb KL, Nixon JA, Hipskind PA (1997) The nonpeptide NK-l receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs. Life Sci 60: 1553–1561PubMedCrossRefGoogle Scholar
- Radhakrishnan V, Henry JL (1991) Novel substance P antagonist, CP-96,345, blocks responses of cat spinal dorsal horn neurons to noxious cutaneous stimulation and to substance P. Neurosci Lett 132: 39–43PubMedCrossRefGoogle Scholar
- Radhakrishnan V, Iyengar S, Henry JL (1998) The nonpeptide NK-1 receptor antagonists LY303870 and LY306740 block the responses of spinal dorsal horn neurons to substance P and to peripheral noxious stimuli. Neuroscience 83: 1251–1260PubMedCrossRefGoogle Scholar
- Reinhardt RR, Laub JB, Fricke JR et al. (1998) Comparison of the neurokinin-1 antagonist, L-754,030, to placebo, acetaminophen and ibuprofen in the dental pain model. Clin Pharmacol Ther 63: 168Google Scholar
- Rupniak NM, Boyce S, Williams AR, Cook G, Longmore J, Seabrook GR, Caeser M, Iversen SD, Hill RG (1993) Antinociceptive activity of NK1 receptor antagonists: nonspecific effects of racemic RP67580. Br J Pharmacol 110: 1607–1613PubMedCrossRefGoogle Scholar
- Rupniak NM, Carlson E, Boyce S, Webb JK, Hill RG (1996) Enantioselective inhibition of the formalin paw late phase by the NK]receptor antagonist L-733,060 in gerbils. Pain 67: 189–195PubMedCrossRefGoogle Scholar
- Rupniak NM, Tattersall FD, Williams AR, Rycroft W, Carlson EJ, Cascieri MA, Sadowski S, Ber E, Hale JJ, Mills SG, MacCoss M, Seward E, Huscroft I, Owen S, Swain CJ, Hill RG, Hargreaves RJ (1997) In vitro and in vivo predictors of the anti-emetic activity Of tachykinin NK1 receptor antagonists. Eur J PharmacoI 326: 201–209CrossRefGoogle Scholar
- Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, MacKillip F (1994) Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 37: 1593–1601PubMedCrossRefGoogle Scholar
- Sabino MA, Honore P, Rogers SD, Mach DB, Luger NM, Mantyh PW (2002) Tooth extraction-induced internalization of the substance P receptor in trigeminal nucleus and spinal cord neurons: imaging the neurochemistry of dental pain. Pain 95: 175–186PubMedCrossRefGoogle Scholar
- Sakai K, Matsuno H, Tsuji H, Tohyama M (1998) Substance Preceptor (NK1) gene expression in synovial tissue in rheumatoid arthritis and osteoarthritis. Scand J Rheumatol 27: 135–141PubMedCrossRefGoogle Scholar
- Schwei MJ, Honore P, Rodgers SD, Salak-johnson JL, Finke MP, Ramnaraine ML, Clohisy DR, Mantyh PW (1999) Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 19: 10886–10897PubMedGoogle Scholar
- Seguin L, Millan MJ (1994) The glycine B receptor partial agonist, (+)−HA966, enhances induction of antinociception by RP 67580 and CP-99,994. Eur J Pharmacol 253: R1R3CrossRefGoogle Scholar
- Sergeyev V, Hökfelt T, Hurd Y (1999) Serotonin and substance P co-exist in dorsal raphe neurons of the human brain. Neuroreport 10: 3967–3970PubMedCrossRefGoogle Scholar
- Shepheard SL, Williamson DJ, Hill RG, Hargreaves RJ (1993) The non-peptide neurokinin, receptor antagonist, RP 67580, blocks neurogenic plasma extravasation in the dura mater of rats. Br J Pharmacol 108: 11–12PubMedCrossRefGoogle Scholar
- Shepheard SL, Williamson DJ, Williams J, Hill RG, Hargreaves RJ (1995) Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in Dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats. Neuropharmacology 34: 255–261PubMedCrossRefGoogle Scholar
- Urban L, Gentry C, Patel S et al. (1999) Selective NK1 receptor antagonists block neuropathic and inflammatory pain in the guinea pig. Proceedings of the 9th World Congress on Pain, IASP Press, Seattle, abstract 125, p 40Google Scholar
- Urban LA, Fox AJ (2000) NK1 receptor antagonists—are they really without effect in the pain clinic? Trends Pharmacol Sci 21: 462–464PubMedCrossRefGoogle Scholar
- Williamson DJ, Shepheard SL, Hill RG, Hargreaves RJ (1997) The novel anti-migraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur J Pharmacol 328: 61–64PubMedCrossRefGoogle Scholar
- Wilson SG, Bryant CD, Lariviere, Olsen MS, Giles BE, Chesler EJ, Mogil JS (2003) The heritability of antinociception II: pharmacogenetic mediation of three over-the-counter analgesics in mice. J Pharmacol Exp Ther 305: 755–764PubMedCrossRefGoogle Scholar
- Yamamoto T, Yaksh TL (1991) Stereospecific effects of a nonpeptidic NK1 selective antagonist, CP-96,345: antinociception in the absence of motor dysfunction. Life Sci 49: I955–I963CrossRefGoogle Scholar
- Yasuda T, Iwamoto T, Ohara M, Sato S, Kohri H, Noguchi K, Senba E (1999) The novel analgesic compound OT-7l00 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazo-lo [1,5-a]pyramid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia. Jpn J Pharmacol 79: 65–73PubMedCrossRefGoogle Scholar