Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility

cross-talk between kappa-opioid and cannabinoid CB(1) receptors

R Capasso, F Borrelli, M G Cascio, G Aviello, K Huben, J K Zjawiony, P Marini, B Romano, V Di Marzo, F Capasso, A A Izzo

Research output: Contribution to journalArticle

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Abstract

BACKGROUND AND PURPOSE: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.

EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.

KEY RESULTS: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.

CONCLUSIONS AND IMPLICATIONS: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

Original languageEnglish
Pages (from-to)681-689
Number of pages9
JournalBritish Journal of Pharmacology
Volume155
Issue number5
DOIs
Publication statusPublished - Nov 2008

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salvinorin A
Ileitis
Salvia
Cannabinoids
Opioid Analgesics
kappa Opioid Receptor
rimonabant
(trans)-Isomer 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide
Croton Oil
Cannabinoid Receptors
Inflammation
Gastrointestinal Motility
Narcotic Antagonists
Irritants
Small Intestine

Keywords

  • Amidohydrolases
  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Croton Oil
  • Diterpenes, Clerodane
  • Electric Stimulation
  • Gastrointestinal Motility
  • Ileitis
  • Intestine, Small
  • Male
  • Mice
  • Mice, Inbred ICR
  • Plant Leaves
  • Protein Binding
  • Receptor Cross-Talk
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, Opioid, kappa
  • Salvia
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility : cross-talk between kappa-opioid and cannabinoid CB(1) receptors. / Capasso, R; Borrelli, F; Cascio, M G; Aviello, G; Huben, K; Zjawiony, J K; Marini, P; Romano, B; Di Marzo, V; Capasso, F; Izzo, A A.

In: British Journal of Pharmacology, Vol. 155, No. 5, 11.2008, p. 681-689.

Research output: Contribution to journalArticle

Capasso, R, Borrelli, F, Cascio, MG, Aviello, G, Huben, K, Zjawiony, JK, Marini, P, Romano, B, Di Marzo, V, Capasso, F & Izzo, AA 2008, 'Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB(1) receptors', British Journal of Pharmacology, vol. 155, no. 5, pp. 681-689. https://doi.org/10.1038/bjp.2008.294
Capasso, R ; Borrelli, F ; Cascio, M G ; Aviello, G ; Huben, K ; Zjawiony, J K ; Marini, P ; Romano, B ; Di Marzo, V ; Capasso, F ; Izzo, A A. / Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility : cross-talk between kappa-opioid and cannabinoid CB(1) receptors. In: British Journal of Pharmacology. 2008 ; Vol. 155, No. 5. pp. 681-689.
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abstract = "BACKGROUND AND PURPOSE: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.KEY RESULTS: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.CONCLUSIONS AND IMPLICATIONS: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.",
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T1 - Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility

T2 - cross-talk between kappa-opioid and cannabinoid CB(1) receptors

AU - Capasso, R

AU - Borrelli, F

AU - Cascio, M G

AU - Aviello, G

AU - Huben, K

AU - Zjawiony, J K

AU - Marini, P

AU - Romano, B

AU - Di Marzo, V

AU - Capasso, F

AU - Izzo, A A

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N2 - BACKGROUND AND PURPOSE: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.KEY RESULTS: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.CONCLUSIONS AND IMPLICATIONS: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

AB - BACKGROUND AND PURPOSE: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.EXPERIMENTAL APPROACH: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.KEY RESULTS: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.CONCLUSIONS AND IMPLICATIONS: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

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KW - Diterpenes, Clerodane

KW - Electric Stimulation

KW - Gastrointestinal Motility

KW - Ileitis

KW - Intestine, Small

KW - Male

KW - Mice

KW - Mice, Inbred ICR

KW - Plant Leaves

KW - Protein Binding

KW - Receptor Cross-Talk

KW - Receptor, Cannabinoid, CB1

KW - Receptor, Cannabinoid, CB2

KW - Receptors, Opioid, kappa

KW - Salvia

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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M3 - Article

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JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

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