Preferencje help
Widoczny [Schowaj] Abstrakt
Liczba wyników
2016 | 76 | 3 |

Tytuł artykułu

The false-positive responses of analgesic drugs to the intradermal serotonin- and compound 48/80-induced scratches as an animal model of itch

Warianty tytułu

Języki publikacji



Intradermal injection of pruritogens such as serotonin, histamine and compound 48/80 into the skin and then, the evaluation of the scratching behavior is the commonly used animal model to advance pruritic research and drug development. However, predictive validity of this model is poorly documented. There is a close interaction between itch and pain sensations with regard to mediation through an anatomically and functionally identical neuronal pathway. One approach is whether the existing animal model of itch differentiates itch or pain to show efficacy of clinically effective analgesic drugs as a back translation. In this study, we explored the effects of different group of analgesic drugs on serotonin and compound 48/80-induced scratching behavior in Balb-C mice. Serotonin (25 μg) and compound 48/80 (100 μg) was injected intradermally in a volume of 50 μl into the rostral part of skin on the back of male mice and scratches were counted for a 30-min observation period. Morphine (1, 3, 10 mg/kg), tramadol (20, 40, 80 mg/kg), cannabinoid agonist CP 55,940 (0.1, 0.3, 1 mg/kg), paracetamol (100, 200, 300 mg/kg) and diclofenac (50, 100, 200 mg/kg) were given intraperitoneally 30 min prior to pruritogen injection. The analgesic drugs dose dependently blocked serotonin and compound 48/80-induced straching behavior with exerting complete inhibition at certain doses. Our data suggests that intradermal pruritogen-induced scratching models may not discriminate pain and itch sensations and give false positive results when standard analgesic drugs are used.

Słowa kluczowe








Opis fizyczny



  • Department of Pharmacology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
  • Department of Pharmacology, Gulhane Military Academy of Medicine, Etlik, Ankara, Turkey
  • Department of Pharmacology, Gulhane Military Academy of Medicine, Etlik, Ankara, Turkey
  • Department of Laboratory Animal Health Center for Research and Development, Gulhane Military Medical Academy, Ankara, Turkey
  • Department of Medical Pharmacology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Department of Dermatology, Gulhane School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey
  • Department of Laboratory Animal Health Center for Research and Development, Gulhane Military Medical Academy, Ankara, Turkey
  • Department of Pharmacology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
  • Department of Pharmacology, Gulhane Military Academy of Medicine, Etlik, Ankara, Turkey
  • Department of Physiology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
  • Department of Pharmacology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey


  • Akiyama T, Carstens MI, Carstens E (2010) Differential itch- and pain-related behavioral responses and micro-opoid modulation in mice. Acta Derm Venereol 90(6): 575–581.
  • Andoh T, Kuraishi Y (1998) Intradermal leukotriene B4, but not prostaglandin E2, induces itch-associated responses in mice. Eur J Pharmacol 353(1): 93–96.
  • Atanassoff PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, Lamotte RH (1999) Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res 16(4): 291–298.
  • Aydin ON, Ek RO, Temoçin S, Uğur B, Alaçam B, Şen S (2012) The antinociceptive effects of systemic administration of tramadol, gabapentin and their combination on mice model of acute pain. Agri 24(2): 49–55.
  • Ballantyne JC, Loach AB, Carr DB (1988) Itching after epidural and spinal opiates. Pain 33(2): 149–160.
  • Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, Schmitt JM, Walker EC, Jones EA (1995) Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med 123(3): 161–167.
  • Brune A, Metze D, Luger TA, Ständer S (2004) Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients. Hautarzt 55(12): 1130–1136.
  • Budzinska K, Andrzejewski K (2014) Respiratory activity in the 6-hydroxydopamine model of Parkinson’s disease in the rat. Acta Neurobiol Exp (Wars) 74(1): 67–81.
  • Byas-Smith MG, Bennett GJ, Gracely RH, Max MB, Robinovitz E, Dubner R (1999) Tourniquet constriction exacerbates hyperalgesia-related pain induced by intradermal capsaicin injection. Anesthesiology 91(3): 617–625.
  • Carstens E, Akiyama T (2014) Itch: Mechanisms and Treatment. Frontiers in Neuroscience. Boca Raton CRC Press/Taylor & Francis, London–New York. Chang WK, Wu HL, Yang CS, Chang KY, Liu CL, Chan KH, Sung CS (2013) Effect on pain relief and inflammatory response following addition of tenoxicam to intravenous patient-controlled morphine analgesia: a double-blind, randomized, controlled study in patients undergoing spine fusion surgery. Pain Med 14(5): 736–748.
  • Colbert S, O’Hanlon DM, Galvin S, Chambers F, Moriarty DC (1999) The effect of rectal diclofenac on pruritus in patients receiving intrathecal morphine. Anaesthesia 54(10): 948–952.
  • Cousins MJ, Mather LE (1984) Intrathecal and epidural administration of opioids. Anesthesiology 61(3): 276–310.
  • Davidson S, Giesler GJ (2010) The multiple pathways for itch and their interactions with pain. Trends Neurosci 33(12): 550–558.
  • De Castro-Costa M, Gybels J, Kupers R, Van Hees J (1987) Scratching behaviour in arthritic rats: a sign of chronic pain or itch?. Pain 29(1): 123–131.
  • Denayer T, Stöhrn T, Van Roy M (2014) Animal models in translational medicine: Validation and prediction. New Horiz Transl Med 2(1): 5–11.
  • Dvorak M, Watkinson A, McGlone F, Rukwied R (2003) Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res 52(6): 238–245.
  • Gobira PH, Ropke J, Aguiar DC, Crippa JA, Moreira FA (2013) Animal models for predicting the efficacy and side effects of antipsychotic drugs. Rev Bras Psiquiatr 35 Suppl 2: S132–S139.
  • Gomes LO, Hara DB, Rae GA (2012) Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci 91(13–14): 628–633.
  • Green AD, Young KK, Lehto SG, Smith SB, Mogil JS (2006) Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 124(1–2): 50–58.
  • Green BG (1990) Spatial summation of chemical irritation and itch produced by topical application of capsaicin. Percept Psychophys 48(1): 12–18.
  • Groene D, Martus P, Heyer G (2001) Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol 10(2): 10–117.
  • Hachisuka J, Ross SE (2014) Understanding the switch from pain-to-itch in dermatitis. Neurosci Lett 579: 188–189.
  • Han L, Dong X (2014) Itch mechanisms and circuits. Annu Rev Biophys 43: 331–355.
  • Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, Lamotte RH, Dong X (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16: 174–182.
  • Haruna T, Soga M, Morioka Y, Hikita I, Imura K, Furue Y, Yamamoto M, Imura C, Ikeda M, Yamauchi A, Deguchi M, Shichijo M, Arimura A, Yasui K (2016) S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission. Pharmacology 95: 95–103.
  • Heyer G, Ulmer FJ, Schmitz J, Handwerker HO (1995) Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm Venereol 75(5): 348–352.
  • Hossain H, Jahan IA, Islam HS, Kanti DS, Arpona H, Arif A (2013) Phytochemical screening and anti-nociceptive properties of the ethanolic leaf extract of trema cannabina lour. Adv Pharm Bull 3(1): 103–108.
  • Inagaki N, Igeta K, Kim JF, Nagao M, Shiraishi N, Nakamura N, Nagai H (2002) Involvement of unique mechanisms in the induction of scratching behavior in BALB/c mice by compound 48/80. Eur J Pharmacol 448(2–3): 175–183.
  • Jin L, Pan L, Guo Y, Zheng Y, Nie Z, Zhu R (2014) Expression and localization of cannabinoid receptor 1 in rats’ brain treated with acute and repeated morphine. Acta Neurobiol Exp (Wars) 74(3): 288–297.
  • Jinks S, Carstens E (2002) Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior. J Neurophysiol 87 (3): 1280–1289.
  • Kremer AE, Martens JJ, Kulik W, Ruëff F, Kuiper EM, van Buuren HR, van Erpecum KJ, Kondrackiene J, Prieto J, Rust C, Geenes VL, Williamson C, Moolenaar WH, Beuers U, Oude Elferink RP (2010) Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 139(3): 1008–1018.
  • Kuraishi Y, Nagasawa T, Hayashi K, Satoh M (1995) Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 275(3): 229–233.
  • LaMotte RH, Shimada SG, Sikand P (2011) Mouse models of acute, chemical itch and pain in humans. Exp Dermatol 20(10): 778–782.
  • Lavich TR, Cordeiro RS, Silva PM, Martins MA (2005) A novel hot-plate test sensitive to hyperalgesic stimuli and non-opioid analgesics. Braz J Med Biol Res 38(3): 445–451.
  • Liang J, Ji Q, Ji W (2011) Role of transient receptor potential ankyrin subfamily member 1 in pruritus induced by endothelin-1. Neurosci Lett 492(3): 175–178.
  • Miller LL, Picker MJ, Umberger MD, Schmidt KT, Dykstra LA (2012) Effects of alterations in cannabinoid signaling, alone and in combination with morphine, on pain-elicited and pain-suppressed behavior in mice. J Pharmacol Exp Ther 342(1): 177–187.
  • Moser HR, Giesler GJ Jr (2014) Itch elicited by intradermal injection of serotonin, intracisternal injection of morphine, and their synergistic interactions in rats. Neuroscience 274: 119–127.
  • Neff GW, O’Brien CB, Reddy KR, Bergasa NV, Regev A, Molina E, Amaro R, Rodriguez MJ, Chase V, Jeffers L, Schiff E (2002) Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am J Gastroenterol 97(8): 2117–2119. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M (2002) Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 47(1): 28–32.
  • Nilsson HJ, Schouenborg J (1999) Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers. Pain 80(1–2): 103–112.
  • Patti CL, Frussa-Filho R, Silva RH, Carvalho RC, Kameda SR, Takatsu- -Coleman AL, Cunha JL, Abílio VC (2005) Behavioral characterization of morphine effects on motor activity in mice. Pharmacol Biochem Behav 81(4): 923–927.
  • Paus R, Schmelz M, Bíró T, Steinhoff M (2006) Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest 116(5): 1174–1186.
  • Ran R, Gu J, Fu J, Zhong H, Zhao Y, Gu Y, Zhang A, Li G, Wang L, Wang Q (2014) The role of the GABA-A receptor of the adjacent intact dorsal root ganglion neurons in rats with neuropathic pain. Acta Neurobiol Exp (Wars) 74(4): 405–414.
  • Ringkamp M, Meyer R (2014) Pruriceptors. In: Itch: Mechanisms and Treatment. Frontiers in Neuroscience (Carstens E, Akiyama T, Eds.). Boca Raton CRC Press/Taylor & Francis, London–New York.
  • Roca-Vinardell A, Ortega-Alvaro A, Gibert-Rahola J, Micó JA (2003) The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen. Anesthesiology 98(3): 741–747.
  • Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH (2009) Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J Pharmacol Exp Ther 329(1): 314–323.
  • Shimada SG LaMotte RH (2008) Behavioral differentiation between itch and pain in mouse. Pain 139(3): 681–687.
  • Shimada SG, Shimada KA, Collins JG (2006) Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur J Pharmacol 530(3): 281–283.
  • Sikand P, Shimada SG, Green BG, LaMotte RH (2009) Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain 144(1–2): 66–75.
  • Simone DA, Alreja M, LaMotte RH (1991) Psychophysical studies of the itch sensation and itchy skin (“alloknesis”) produced by intracutaneous injection of histamine. Somatosens Mot Res 8(3): 271–279.
  • Simone DA, Baumann TK, LaMotte RH (1989) Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38(1): 99–107.
  • Spradley JM, Davoodi A, Gee LB, Carstens MI, Carstens E (2012) Differences in peripheral endocannabinoid modulation of scratching behavior in facial vs. spinally-innervated skin. Neuropharmacology 63(4): 743–749.
  • Takaoka A, Arai I, Sugimoto M, Futaki N, Sakurai T, Honma Y, Nakaike S (2007) Role of scratch-induced cutaneous prostaglandin D production on atopic-like scratching behaviour in mice. Exp Dermatol 16(4): 331–339.
  • Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura  K, Endoh T, Utsumi J, Kamei J, Tanaka T, Nagase H (2002) Antipruritic activity of the kappa-opioid receptor agonist, TRK-820. Eur J Pharmacol 435(2–3): 259–264.
  • Wang H, Papoiu AD, Coghill RC, Patel T, Wang N, Yosipovitch G (2010) Ethnic differences in pain, itch and thermal detection in response to topical capsaicin: African Americans display a notably limited hyperalgesia and neurogenic inflammation. Br J Dermatol 162(5): 1023–1029.
  • Wojtecka-Lukasik E, Stachurska J, Kopeć M, Maśliński S (1988) Anti- -inflammatory drugs modulate histamine release from mast cells induced by fibrinogen degradation products. Ann Rheum Dis 47(4): 328–332.
  • Yamaguchi T, Nagasawa T, Satoh M, Kuraishi Y (1999) Itch associated response induced by intradermal serotonin through 5-HT2 receptors in mice. Neurosci Res 35(2): 77–83.
  • Zachariae R, Lei U, Haedersdal M, Zachariae C (2012) Itch severity and quality of life in patients with pruritus: preliminary validity of a Danish adaptation of the itch severity scale. Acta Derm Venereol 92(5): 508–514.
  • Zhao H, Luo F, Li H, Zhang L, Yi Y, Wan J (2014) Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKKbeta phosphorylation and the COX-2/PGE(2) pathway in mice. PLoS One 9(4): e94586.

Typ dokumentu



Identyfikator YADDA

JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.