Loperamide: Evidence of interaction with μ and δ opioid receptors

Giagnoni, Gabriella; Casiraghi, Luca; Senini, R.; Revel, Laura; Parolaro, Daniela; Sala, Mariaelvina; Gori, E

doi:10.1016/0024-3205(83)90506-4

Cited by 42 publications

(21 citation statements)

References 10 publications

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“…The antidiarrheal drug loperamide is an agent of the piperidine class known to act as a u-opiate agonist [1,2] and as a calmodulin inhibitor [3]. In the p-opiate system, the dissociation constant for receptor binding and the concentration range of loperamide giving biological activ ity ( 10"9-10'8 M) are similar, as shown for morphine or naloxone [2,3].…”

Section: Introductionmentioning

confidence: 83%

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Auernhammer

Renner

Müller³

et al. 1993

Neuroendocrinology

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The effect of the antidiarrheal drug loperamide, a µ-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2–5 nM) and the membrane-permeable Bu(2)cAMP (0.5–2.5 mM). The protein kinase C pathway was stimulated with 1 µM arginine vaso-pressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 µM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 ± 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomela-nocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 µM). Morphine (0.01-10 µM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu₍₂₎cAMP-induced ACTH secretion in cell culture from 100 ± 4 to 77 ± 4% (p < 0.05). In Ca²⁺-depleted medium (Ca²⁺ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 ± 5 to 74 ± 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide. In comparison with the known effects of the calmodulin-inhibitors trifluoperazine, W-7 and penfluridol, loperamide mimicked all their effects on ACTH secretion. We conclude: (1) the effects of loperamide on corticotrophic cell function in vitro are naloxone-insensitive and not mediated by µ-opiate receptors; and (2) our data provide a strong argument for loperamide working as a calmodulin inhibitor in the rat anterior pituitary in vitro.

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Section: Introductionmentioning

confidence: 83%

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Auernhammer

Renner

Müller³

et al. 1993

Neuroendocrinology

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“…The effects of loperamide on Na uptake by isolated chicken enterocytes are shown in Figs. 4 and 5. Na uptake into the chicken enterocytes, particularly that component regulated by intestinal hormones and neurotransmitters, has been shown to occur predominantly by an amiloridesensitive Na/H exchange in the apical membrane (28)(29)(30).…”

Section: Resultsmentioning

confidence: 99%

“…It binds to opiate receptors present in the intestinal longitudinal muscle and myenteric plexus and alters gut motor activity, an action that is only partially reversed by opiate antagonists such as naloxone (1)(2)(3)(4). Although the antidiarrheal activity of loperamide stems in large part from its effects on intestinal motor function under conditions of normal absorption (5), a portion of these therapeutic actions may be attributed to its ability to alter ion and fluid transport across the intestinal mucosa under secretory conditions (6).…”

Section: Introductionmentioning

confidence: 99%

Secretagogue-induced changes in membrane calcium permeability in chicken and chinchilla ileal mucosa. Selective inhibition by loperamide.

et al. 1986

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Substance P (SP), neurotensin (NT), bombesin (BB), serotonin (5HT), and carbamylcholine (CCH) transiently increase electrogenic anion secretion in chinchilla and chicken ileum. SP and CCH also transiently inhibit amiloride-sensitive Na/H exchange in isolated chicken enterocytes. Loperamide (LP) inhibits the short-circuit current responses caused by SP, NT, and BB, but not those caused by CCH, 5HT, Ca ionophore, or cyclic nucleotides. Similarly, LP inhibits the effects of SP, but not those of CCH, on Na/H exchange.LP inhibition of the SP effects was further studied in isolated chicken enterocytes. CCH and SP transiently increased cytosolic Ca activity by 20-50 nmol/liter, but only the response to SP was inhibited by LP (10-' M) and by the absence of extraceliular Ca. We conclude (a) SP and CCH effects on intestinal electrolyte transport are mediated by increasing enterocyte Ca activity and (b) LP specifically inhibits peptide hormone-activated Ca entry by an opiate receptor-independent mechanism.

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“…These observations, together with recent in vitro [9] and in vivo [4] data indicating that lopera mide acts through p-receptors, might be in favor of a supra pituitary influence of the drug, probably at the median emi nence level, since loperamide can only cross the bloodbrain barrier at very high doses [20]. This effect might involve some hypothalamic factors, which modulate the ACTH response to either CRH or vasopressin differently.…”

Section: Discussionmentioning

confidence: 96%

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

1988

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Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addison’s disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 µg/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 ± 17.3 to a peak of 95 + 21 pmol/l) and placebo (from 231 ± 59.5 to 365 ± 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 ± 16.6 to a peak of 108 ± 31 pmol/l) and placebo (from 98.5 ± 47 to 211 ± 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.

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Loperamide: Evidence of interaction with μ and δ opioid receptors

Cited by 42 publications

References 10 publications

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Loperamide Inhibits Corticotrophic Cell Function by a Naloxone-lnsensitive Mechanism in the Rat in vitro

Secretagogue-induced changes in membrane calcium permeability in chicken and chinchilla ileal mucosa. Selective inhibition by loperamide.

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

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