Effect of repeated administration of TRK-820, a κ-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions

Suzuki, Tomohiko; Izumimoto, Naoki; Takezawa, Yuko; Fujimura, Morihiro; Togashi, Yuko; Nagase, Hiroshi; Tanaka, Toshiaki; Endoh, Takashi

doi:10.1016/j.brainres.2003.09.057

Cited by 31 publications

(25 citation statements)

References 37 publications

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“…Our standard dose of nalfurafine (0.02 mg/kg) did not markedly affect locomotor activity. Previously, Suzuki and his colleagues (2004) reported, in agreement with our results, that behavioral depression was associated only with a higher dose of nalfurafine (0.04 mg/kg) on wheel running in mice.…”

Section: Discussionsupporting

confidence: 93%

Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice

2009

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The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5′-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTIinduced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001-0.03 mg/kg, s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. Tolerance did not develop to the antiscratch activity of nalfurafine. Both GNTI and compound 48/80 provoked c-fos expression on the lateral side of the superficial layer of the dorsal horn of the cervical spinal cord and pretreating mice with nalfurafine inhibited c-fos expression induced by both pruritogens. In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch. Keywords itch; pain; kappa opioid receptor agonist; compound 48/80; kappa opioid receptor antagonist

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Section: Discussionsupporting

confidence: 93%

Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice

2009

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“…Prior studies have found nalfurafine to produce minimal analgesic tolerance in the acetic acid writhing and herpetic pain assays [30,31]. To determine if high doses of nalfurafine are capable of producing analgesic tolerance in the warm water tail withdrawal assay, U50,488-induced increases in tail withdrawal latency were used to measure cross-tolerance at KOR following a pre-injection of nalfurafine.…”

Section: Resultsmentioning

confidence: 99%

Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor

Schattauer

Kuhar

Song

et al. 2017

Cellular Signalling

103

102

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Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38α MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radio ligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5′-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38α MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics.

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“…A 3-day consecutive administration regimen was used for induction Pharmacological Effects of ATPM, a Novel -Opioid Agonist of antinociceptive tolerance of drugs, as reported by Suzuki et al (2004) previously. Morphine (2.5-10 mg/kg), (Ϫ)U50,488H (2-8 mg/ kg), or ATPM (1-4 mg/kg) was administrated twice on days 1 and 2 (9:00 AM and 4:00 PM) and once on day 3 (09:00).…”

Section: Antinociceptive Tolerance Assaysmentioning

confidence: 99%

“…Next, the potential of ATPM to develop antinociceptive tolerance was determined with the protocol reported by previous study (Suzuki et al, 2004). Mice were subcutaneously administered with various doses of ATPM (1, 2, and 4 mg/kg), (Ϫ)U50,488H (2, 4, and 8 mg/kg), or morphine (2.5, 5, and 10 mg/kg) twice daily for 3 consecutive days, respectively, and on day 4, a single dose of each compound was used to determine its tolerant ED 50 value.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

Wang

Tao²,

Li³

et al. 2009

J Pharmacol Exp Ther

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ATPM [(Ϫ)-3-amino-thiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed -and -opioid activity and identified to act as a full -agonist and a partial -agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (Ϫ)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by -and -, but not ␦-opioid, receptors. In addition to its agonist profile on the -receptor, ATPM also acted as a -antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED 50 value of sedation to that of antinociception than (Ϫ)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (Ϫ)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (Ϫ)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (Ϫ)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed -agonist and -agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect.-Agonists with some -activity appear to offer some advantages over selective -agonists for the treatment of heroin abuse.Previous studies in both nonhuman primates and rats have demonstrated that -agonists functionally attenuate many behavioral effects of cocaine, including behavioral sensitization (Ukai et al

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Effect of repeated administration of TRK-820, a κ-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions

Cited by 31 publications

References 37 publications

Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice

Nalfurafine prevents 5′-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5′-guanidinonaltrindole-elicited scratching behavior in mice

Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

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