Antipruritic activity of the κ-opioid receptor agonist, TRK-820

Togashi, Yuko; Umeuchi, Hideo; Okano, Kiyoshi; Ando, Naoki; Yoshizawa, Yoshitaka; Honda, Toshiyuki; Kawamura, Kuniaki; Endoh, Takashi; Utsumi, Jun; Kamei, Junzo; Tanaka, Toshiaki; Nagase, Hiroshi

doi:10.1016/s0014-2999(01)01588-6

Cited by 198 publications

(134 citation statements)

References 27 publications

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“…This anti-pruritic effect may be due to a direct effect in one or more areas of the brain and/or a positive feedback from the skin at the level of the spinal cord. The itching of uremic pruritus may be caused by another pruritogen, substance P. This chemical has been shown to induce scratching in mice, with and without mast cells (14). Antihistamines were not effective in relieving the scratching in either setting.…”

Section: Discussionmentioning

confidence: 99%

“…-Opioid stimulation inhibits -receptor effects both centrally and peripherally (11). Nalfurafine, a new -opioid receptor agonist, was effective in reducing the scratching behavior induced by an injection of substance P in the mouse model (13,14). From these findings, it was hypothesized that uremic pruritus could be triggered and sustained by the release of substance P (15).…”

mentioning

confidence: 99%

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κ-Opioid System in Uremic Pruritus

Wíkström

Gellert²,

Ladefoged³

et al. 2005

Journal of the American Society of Nephrology

271

170

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Uremic pruritus is a very common and frustrating condition for both patients and clinicians because no treatment has been demonstrated to be effective in relieving the itch. In this report, nalfurafine, a new -opioid receptor agonist, was used to treat uremic pruritus in patients who were undergoing routine hemodialysis. Two multicenter, randomized, double-blind, placebocontrolled studies enrolled 144 patients with uremic pruritus to postdialysis intravenous treatment with either nalfurafine or placebo for 2 to 4 wk. A meta-analysis approach was used to assess the efficacy of nalfurafine. Statistically significant reductions in worst itching (P ‫؍‬ 0.0212), itching intensity (P ‫؍‬ 0.0410), and sleep disturbances (P ‫؍‬ 0.0003) were noted in the nalfurafine group as compared with placebo. Improvements in itching (P ‫؍‬ 0.0025) and excoriations (P ‫؍‬ 0.0060) were noted for the nalfurafine-treated patients. Nalfurafine showed similar types and incidences of drug-related adverse events as did placebo. Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population. U remic pruritus has a major impact on the quality of life in patients who already have a compromised lifestyle (1-5). It is, of itself, not a life-threatening condition; however, it is known to contribute to an increase in morbidity (6) and mortality (7) of uremic patients. The only current definitive treatment for uremic pruritus is successful renal transplantation (8). Increasing the dialysis dose as well as implementing other therapeutic measures to lessen the symptoms, some as extraordinary as acupressure, (9) have provided only limited effectiveness in dialysis patients.Stimulation of the -opioid receptor in the brain and/or peripheral nerve endings by its agonists, such as morphine, can result in itching (10 -12). -Opioid receptor antagonists can inhibit itching induced by substance P (13). -Opioid stimulation inhibits -receptor effects both centrally and peripherally (11). Nalfurafine, a new -opioid receptor agonist, was effective in reducing the scratching behavior induced by an injection of substance P in the mouse model (13,14). From these findings, it was hypothesized that uremic pruritus could be triggered and sustained by the release of substance P (15). This led to the studies in the treatment of uremic pruritus using nalfurafine. Materials and Methods Study Design and TreatmentsTwo multicenter, randomized, double-blind, placebo-controlled clinical studies were performed with the common objective of assessing the efficacy and the safety of nalfurafine, as compared with placebo, in the treatment of uremic pruritus. The inclusion and exclusion criteria and the evaluations, methods of evaluations, and times of evaluations were the same in both studies.Patients were males and females who were at least 18 yr of age and undergoing routine hemodialysis secondary to ESRD and had severe, uncontrolled pruritus caused only by ESRD. Female patients were not of childbearing potential or were using an acceptab...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

κ-Opioid System in Uremic Pruritus

Wíkström

Gellert²,

Ladefoged³

et al. 2005

Journal of the American Society of Nephrology

271

170

View full text Add to dashboard Cite

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“…From our findings, we implicate the central nervous system and, more specifically, the dorsal striatum in icilin-induced shaking behavior. Nalfurafine (Seki et al, 1999;Togashi et al, 2002;Inan and Cowan, 2004) an effective antipruritic in uremic pruritus (Wikström et al, 2005) should act similarly to other kappa opioid receptor agonists, e.g. U50,488H and U69,593, commonly used in microdialysis studies.…”

Section: Discussionmentioning

confidence: 99%

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

Werkheiser¹,

Cowan²

2007

Neuropharmacology

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Icilin, a cooling compound, produces vigorous wet-dog shakes in rats. We have reported previously that icilin-induced wet-dog shakes are blocked by the kappa opioid receptor agonists, nalfurafine and U50,488H, and that icilin evokes a dose-and time-dependent increase in glutamate within the dorsal striatum. Since activation of kappa opioid receptors inhibits glutamate release intrastriatally, we targeted glutamate release within the dorsal striatum using nalfurafine and examined the role of the dorsal striatum in icilin-induced wet-dog shakes, more specifically, the effect that icilin-evoked intrastriatal glutamate release has on the overt stimulant behavior. We report that nalfurafine (0.04 mg/kg) inhibits icilin (0.50 mg/kg)-induced wet-dog shakes and that this inhibition is reversed by intrastriatal perfusion of the kappa opioid receptor antagonist, norbinaltorphimine (100 nM). Furthermore, we antagonized icilin-evoked glutamate release with nalfurafine (0.04 mg/kg), and reversed inhibition of glutamate release with intrastriatal norbinaltorphimine (100 nM). These findings support a central component in the behavioral response to icilin and suggest that activation of kappa opioid receptors antagonizes icilin-induced wet-dog shakes in rats by inhibiting glutamate release within the dorsal striatum.

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“…administration of TRK-820 dose-dependently inhibited scratching behavior induced by histamine in mice, which is one of the representative pruritogenic substances, without obvious suppression of spontaneous locomotor activity. The antiscratching activity of TRK-820 with ED 50 7.3 g/kg was antagonized by nor-BNI (Togashi et al, 2002). TRK-820 was effective in scratching induced by the other pruritogenic substances: substance P (Togashi et al, 2002;Umeuchi et al, 2003;Utsumi et al, 2004), chloroquine (Inan & Cowan, 2004), compound 48/80 (Wang, Y et al, 2005), agmatin (Inan & Cowan, 2006a), and 5'-GNTI (Inan et al, 2009a(Inan et al, , 2011 (Table 8).…”

Section: Antipruritic Effects 41 Preclinical Studiesmentioning

confidence: 97%