Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice

doi:10.1016/S0168-0102(99)00070-X

Neuroscience Research

Volume 35, Issue 2, November 1999, Pages 77-83

https://doi.org/10.1016/S0168-0102(99)00070-X Get rights and content

Abstract

Serotonin (5-HT) is pruritogenic in humans and suggested to be involved in some pruritic diseases. Our experiments were carried out to determine whether an intradermal injection of 5-HT would elicit itch-associated response in mice and to elucidate the 5-HT receptor subtypes involved in this 5-HT action. 5-HT (14.1–235 nmol site⁻¹) injected intradermally into the rostral back elicited scratching of the injected site, with bell-shaped dose-response relationship. The scratching induced by 5-HT (100 nmol site⁻¹, peak effective dose) was suppressed by capsaicin (repeated administration) and the opioid antagonist naloxone, features being similar to human itching. Scratching was also elicited by the 5-HT₂ receptor agonist α-methylserotonin, but not by the 5-HT_1A receptor agonist R(+)-8-hydroxy-N,N-dipropyl-2-aminotetralin nor the 5-HT₃ receptor agonists 2-methylserotonin and 1-phenylbiganide. Scratching induced by 5-HT and α-methylserotonin was inhibited by peroral pretreatment with 5-HT_1/2 receptor antagonists methysergide and cyproheptadine. 5-HT-induced scratching was also inhibited by intradermal injection of methysergide. Peroral pretreatment with 5-HT₃ receptor antagonists ondansetron and 3-tropanyl-3, 5-dichrobenzoate did not significantly suppress 5-HT-induced scratching. The results suggest that scratching induced by intradermal injection of 5-HT is itch-associated response. The 5-HT action may be mediated at least partly by cutaneous 5-HT₂ receptors.

Introduction

Itch is a sensation that is localized to the superficial layers of the skin (Shelley and Arthur, 1957, Keele and Armstrong, 1964) and associated with a desire to scratch the offending area. Itch is the main symptom of cutaneous diseases, such as atopic dermatitis and contact dermatitis, and accompanying several systemic diseases, such as polycythemia vera, chronic renal failure and cholestasis. However, its pathophysiological mechanisms are not clear. When applied to the mouse skin, pruritogenic agents, such as compound 48/80 and substance P, elicit scratching of the treated skin, while algesiogenic agents, such as capsaicin and formalin, are without apparent behavioral effects (Kuraishi et al., 1995). Thus, compound 48/80- and substance P-induced scratching may not be due to pain. Scratching induced by substance P has features similar to human itching; for example, the opioid antagonist naloxone inhibits substance P-induced scratching in mice (Andoh et al., 1998) and an itch sensation induced by histamine in human subjects (Bernstein et al., 1982). On the other hand, naloxone enhances pain behavioral responses in rodents (Jacob and Ramabadran, 1978, Sugimoto et al., 1986). These findings taken together suggest that substance P-induced scratching is an itch-associated response.

Although histamine is a classical itch mediator in humans (Armstrong et al., 1953, Wahlgren and Ekblom, 1991), it does not elicit the itch-associated response in mice (Kuraishi et al., 1995), suggesting that this amine is not a primary itch mediator in mice. Serotonin (5-HT) produces an itch sensation when applied to the human skin (Fjellner and Hägermark, 1979, Weisshaar et al., 1997) and has been suggested to be involved in itch of pruritic diseases, such as polycythemia vera (Fitzsimons et al., 1981) and cholestasis (Schwörer et al., 1995). To investigate pruritogenic activity of 5-HT in animals, we examined whether an intradermal (ID) injection of 5-HT would elicit itch-associated behaviors in mice and determined the 5-HT receptor subtypes involved in this response.

Section snippets

Materials

Serotonin hydrochloride, capsaicin, naloxone hydrochloride and cyproheptadine hydrochloride were purchased from Sigma (St. Louis, MO) and histamine was from Wako Pure Chemical (Osaka, Japan). 1-Phenylbiganide, 2-methylserotonin maleate, R(+)-8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT), α-methylserotonin maleate, methysergide maleate and 3-tropanyl-3, 5-dichrobenzoate (MDL-72222) were from Research Biochemical International (Massachusetts, USA). Ondansetron was a gift from

Scratching after 5-HT and histamine

When injected ID into the rostral back, 5-HT elicited scratching of the injected site and the surrounding region by the hind paws. Fig. 1 shows an example of scratching responses to 5-HT (141 nmol site⁻¹=30 μg site⁻¹). Although 5-HT at a dose of 1.41 nmol site⁻¹ was without apparent effect, 5-HT (14.1–141 nmol site⁻¹) produced a dose-dependent increase in scratching (Fig. 2). The effect of higher dose of 235 nmol site⁻¹ was significant but much less than that of 141 nmol site⁻¹. The median of

Discussion

We demonstrated that an ID injection of 5-HT, but not histamine, into the rostral back of the mouse elicited scratching of the injected site and surrounding skin by the hind paws. Such 5-HT injection did not elicit the scratching of the face and ID injection of this amine into the caudal back, a region the mouse can not scratch, did not induce the scratching of the rostral back. These results suggest that ID injection of 5-HT induced scratching through local skin stimulation and that this

Acknowledgements

This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, sports and Culture of Japan.

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Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice

Abstract

Introduction

Section snippets

Materials

Scratching after 5-HT and histamine

Discussion

Acknowledgements

Life Sci.

Pain

Gastroenterology

J. Invest. Dermatol.

J. Am. Acad. Dermatol.

Brain Res.

Eur. J. Pharmacol.

J. Dermatol. Sci.

Trends Neurosci.

J. Am. Acad. Dermatol.

Neuroscience

Pain

Neuropharmacology

Brain Res.

Brain Res.

Brain Res.

J. Am. Acad. Dermatol.

Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice

J. Pharmacol. Exp. Ther.

Observation on chemical excitants of cutaneous pain in man

J. Physiol.

Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial

Ann. Intern. Med.

Ondansetron for the treatment of pruritus after spinal opioids

Anaesthesia

Itch-associated response induced by intradermal serotonin through 5-HT₂ receptors in mice

Substance P induction of itch-associated response mediated by cutaneous NK₁ tachykinin receptors in mice