Pierre J.M. Rivière

The University of Arizona, Tucson, Arizona, United States

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Publications (17)73.14 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: This study investigates two new K-agonist tetrapeptides, FE 200665 and FE 200666, with high peripheral selectivity as a result of poor central nervous system penetration, Methods: Four days after administration of Freund adjuvant into the hind paw of male Wistar rats, antinociceptive effects of intraplantar and subcutaneous injection of FE 200665 and FE 200666 were measured by paw pressure algesiometry and compared with the K-agonist U-69,593. Peripheral and K-receptor selectivity was assessed by the antagonists naloxone methiodide (NLXM) and nor-binaltorphimine, respectively. Antiinflammatory effects were evaluated by paw volume plethysmometry and histologic score. Results: Similar to intraplantar U-69,593, intraplantar FE 200665 (3-100 mug) and FE 200666 (1-30 mug) resulted in significant and dose-related increases of paw pressure thresholds. Higher doses of FE 200665 (0.2-20 mg) and FE 200666 (0.06-6 mg) were required by subcutaneous route to produce similar antinociceptive responses, supporting a peripheral site of action. nor-Binaltorphimine dose-dependently antagonized this effect, implying K-opioid selectivity. Analgesic effects of subcutaneous FE 200665 and FE 200666 were abolished by intraplantar nor-binaltorphimine, and both subcutaneous and intraplantar effects were dose-dependently antagonized by subcutaneous NLXM, further demonstrating a peripheral site of action. One to 6 days after Freund adjuvant inoculation, single and repeated intraplantar injections of FE 200665, FE 200666, and U-69,593 significantly reduced paw volume and histologic scores. Both changes were reversed by intraplantar nor-binaltorphimine and subcutaneous NLXM. Conclusion: FE 200665 is a peripherally selective K-agonist with potent analgesic and antiinflammatory properties that may lead to improved analgesic-antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.
    Anesthesiology 05/2001; 94(6):1034-1044. DOI:10.1097/00000542-200106000-00018 · 6.17 Impact Factor
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    ABSTRACT: Fedotozine is a kappa opioid receptor agonist having antinociceptive properties but devoid of diuretic effects. The aim of the study was to evaluate the discriminative stimulus effects of fedotozine at doses previously reported to produce maximal effects in in vivo assays measuring kappa-mediated analgesia. By using a two-lever drug discrimination task, two groups of rats were trained to discriminate either a 3 mg/kg i.p. dose of the kappa opioid agonist, U50,488, or a 5 mg/kg i.p. dose of the mu opioid agonist, morphine, from saline. Once trained, rats were used to conduct tests of stimulus generalization with morphine, U50,488 and fedotozine along with another kappa agonist, CI-977, and another mu agonist, fentanyl. The stimulus effect of U50,488 was shared by CI-977 but not by morphine. Conversely, the stimulus effect of morphine was shared by fentanyl but not by U50,488. Fedotozine (1-10 mg/kg) failed to substitute to either U50,488 or morphine. These results indicate that, when administered at doses fully effective in producing antinociception, the interoceptive stimulus effects of fedotozine, if any, can be distinguished from those produced by U50,488 and morphine.
    European Neuropsychopharmacology 01/1999; 8(4):261-6. DOI:10.1016/S0924-977X(97)00084-9 · 5.40 Impact Factor
  • H. Fargeau, P. J. M. Rivière, J. L. Junien, M. Chovet
    Gastroenterology 04/1998; 114(4). DOI:10.1016/S0016-5085(98)81490-X · 13.93 Impact Factor
  • Gastroenterology 04/1998; 114(4). DOI:10.1016/S0016-5085(98)84609-X · 13.93 Impact Factor
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    ABSTRACT: This study investigates the contribution of prostaglandins (PG) and calcitonin gene-related peptide (CGRP) pathways in visceral pain induced by peritoneal irritation in rats. Peritoneal irritation was produced by i.p. administration of acetic acid (AA: 0.06-1.0%, 10 ml/kg). Visceral pain was scored by counting abdominal contractions. The effect of CGRP (3-100 microg/kg, i.p.) was also evaluated. Like AA, CGRP induced abdominal pain. Neonatal pretreatment with capsaicin reduced abdominal contractions produced by AA (0.6%) and CGRP (20 microg/kg) with 64.6% and 45.6%, respectively. Abdominal contractions induced by AA and CGRP were blocked by two antinociceptive drugs, mu-and kappa-opioid agonists, morphine and (+/-)-U-50,488H, respectively. Indomethacin (3 mg/kg, s.c.) reduced the number of abdominal contractions produced by AA by 78.1%+/-6.4% but did not inhibit abdominal contractions produced by CGRP. The CGRP, receptor antagonist, hCGRP(8-37) (300 microg/kg, i.v.) inhibited AA- and CGRP-induced abdominal contractions with 57.5%+/-12.4% and 51.6%+/-11.3%, respectively. Concomitant i.p. administration of PGE1 and PGE2 (0.3 mg/kg of each) produced abdominal contractions which were inhibited 45.6%+/-9.3% by hCGRP(8-37) (300 microg/kg i.v.). Taken together, these results suggest that peritoneal irritation is likely to trigger the release of prostaglandins, which in turn produces a release of CGRP from primary sensory afferents.
    Regulatory Peptides 06/1997; 70(1):1-7. DOI:10.1016/S0167-0115(97)02141-1 · 2.01 Impact Factor
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    ABSTRACT: The effect of fedotozine on visceral hypersensitivity was evaluated in conscious rats. One hour after colonic irritation (0.6% acetic acid intracolonically), a 30 mmHg colonic distension was applied for 10 min. Irritation increased the number of abdominal contractions induced by colonic distension (23.4 +/- 4.1 versus 4.8 +/- 1.4 in saline-treated rats, P < 0.001). Facilitation of colonic pain was reversed in a dose-dependent manner by fedotozine ((+)-(-1R1)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N ,N-dimethyl-n-propylamine), (+/-)-U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl]cyclohexyl)benzen eacetamide) and morphine (respective ED50 values 0.67, 0.51 and 0.23 mg/kg s.c.). The kappa-opioid receptor antagonist, nor-binaltorphimine, abolished the effects of fedotozine and (+/-)-U-50,488H but not those of morphine. Low doses of naloxone (30 microg/kg s.c.) blocked the effect of morphine but not of fedotozine or (+/-)-U-50,488H. After intracerebroventricular administration, morphine was very potent (ED50 1.7 microg/rat), (+/-)-U-50,488H poorly active (58% of antinociception at 300 microg/rat) and fedotozine inactive up to 300 microg/rat. These results show that fedotozine blocks hypersensitive visceral pain by acting on peripheral kappa-opioid receptors in animals.
    European Journal of Pharmacology 05/1997; 324(2-3):211-7. DOI:10.1016/S0014-2999(97)00089-7 · 2.68 Impact Factor
  • N Friese, L Diop, C Lambert, P.J.M. Rivière, S G Dahl
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    ABSTRACT: The antinociceptive activity of the kappa- and mu-opioid receptor agonists, (+/-)-U-50,488H and morphine, was examined in a vaginal distension model in anaesthetized female rats. Vaginal distension induced a reproducible cardiovascular response (CVR) which was inhibited in a dose related manner by morphine (0.03-1.0 mg/kg i.v., ED50 = 0.16 mg/kg) and (+/-)-U-50,488H (0.08-1.6 mg/kg i.v., ED50 = 0.49 mg/kg). Morphine (0.3 microg/rat) administered i.c.v. inhibited the CVR by 81.6 +/- 7.9% whereas (+/-)-U-50,488H (30-300 microg/rat) was inactive by this route. A low dose of naloxone (30 microg/kg i.v.) blocked the effect of morphine but not that of (+/-)-U-50,488H. The kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg s.c.) abolished the response to (+/-)-U-50,488H but not that of morphine. This demonstrates that both central and peripheral mu-opioid receptors may be involved in morphine-induced antinociception whereas the kappa-opioid agonist, (+/-)-U-50,488H, blocks vaginal nociception by acting on peripheral kappa-opioid receptors.
    Life Sciences 02/1997; 61(16):1559-70. DOI:10.1016/S0024-3205(97)00735-2 · 2.30 Impact Factor
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    ABSTRACT: Peritoneal irritation in rats induced by i.p. administration of acetic acid produces abdominal contractions reflecting visceral pain, and gastrointestinal ileus characterized by inhibition of gastric emptying and small intestine transit. In this study, gastric emptying (GE) and intestinal transit, calculated by the geometric center (GC) method, were estimated using a test meal labeled with 51Cr-EDTA. Visceral pain was assessed by counting abdominal contractions. Acetic acid produced abdominal contractions (80.8 +/- 3.3) and inhibition of GE (-54%) and GC (-63%) during the test-period. The kappa-opioid receptor agonists, CI-977 (+/-)-U-50,488H, (+/-)-bremazocine, PD-117,302, (-)-cyclazocine, and U-69,583, reversed abdominal contractions and inhibitions of gastrointestinal transit in a dose-related manner. The mu-opioid receptor agonists and potent analgesics, morphine and fentanyl did not restore normal gastric emptying and intestinal transit. These data suggest that selective kappa-opioid receptor agonists might be used to treat abdominal pain associated with motility and transit impairment during postoperative ileus.
    Life Sciences 02/1997; 60(9):625-34. DOI:10.1016/S0024-3205(96)00647-9 · 2.30 Impact Factor
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    ABSTRACT: Subcutaneous administration of granisetron (BRL 43694, endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl-1 H-indazole-3-carboxamide) and zacopride (4-amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-5-chloro-2-methoxybenzamide), two 5-HT3 receptor antagonists, at doses ranging from 3 to 1000 micrograms/kg, inhibited abdominal contractions induced by distension (30 mmHg, 10 min) of irritated colon (0.6% acetic acid) in conscious rats with a bell-shaped dose-response curve. The ED50 of granisetron and zacopride were 17.6 and 8.2 micrograms/kg, respectively. In contrast, both tropisetron (ICS 205-930, (3-a-tropanyl)t-indole-3-carboxylic ester) and ondansetron (GR38032F, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)methyl]-4 H-carbazol-4-one hydrocloride dihydrate) were inactive in this model. These data further support the concept of a heterogeneity in the potency of 5-HT3 receptor antagonists in modulating visceral hypersensitivity in conscious rats. This finding is in agreement with a reported efficacy of granisetron but not of ondansetron in patients with irritable bowel syndrome.
    European Journal of Pharmacology 01/1997; 318(1):141-4. DOI:10.1016/S0014-2999(96)00857-6 · 2.68 Impact Factor
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    ABSTRACT: The possible involvement of nitric oxide in the regulation of intestinal ion transport induced by neuropeptide Y (NPY) was investigated by evaluating the effects of NG-methyl-L-arginine (L-NMA), L-arginine and S-nitroso-N-acetylpenicillamine (SNAP) on NPY activity in mouse ileum mounted in Ussing chambers in vitro. Serosal NPY (10 nM) produced a sustained decrease in basal transmural short circuit current (Isc) and potential difference without altering the tissue conductance. Pretreatment of tissues with L-arginine (3 mM), but not D-arginine (10 mM), blocked the NPY-mediated changes in Isc. This L-arginine effect on NPY activity was reversed by L-NMA (3 mM), and not by NG-methyl-D-arginine (10 mM). The L-arginine effect on NPY activity was concentration-related with an A50 (95% CL) value of 1.6 (0.9-2.3) mM. In contrast to L-arginine, L-NMA (1 mM) pretreatment of tissues produced an enhancement of NPY activity, resulting in a 3.8-fold leftward displacement of the NPY concentration-response curve; NG-methyl-D-arginine was without effect. The effect of L-NMA on NPY activity was concentration-related with an A50 (95% CL) value of 45.3 (23.2-68.8) microM. Serosal application of SNAP, a nitric oxide donor, produced a concentration-related decrease in basal Isc and potential difference without altering tissue conductance with an A50 (95% CL) value of 22.5 (11.1-40.5) microM. Pretreatment of tissue with SNAP (100 microM) reduced the NPY activity with rightward displacement of NPY concentration-response curve. Pretreatment of tissues with L-arginine also blocked the reduction of Isc by [D-Pen2, D-Pen5]enkephalin (10-30 nM), H2N-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 (10-30 nM) and somatostatin (0.3-1.0 microM), but had no effect on norepinephrine (0.1-0.3 microM)-induced decrease in mouse ileal Isc. These results show that [fgc]l-arginine and SNAP block NPY-mediated changes in ion transport, suggesting that nitric oxide may play a role in the regulation of NPY-mediated ion transport in the mouse ileum.
    Journal of Pharmacology and Experimental Therapeutics 08/1996; 278(1):193-8. DOI:10.1016/0143-4179(94)90179-1 · 3.86 Impact Factor
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    ABSTRACT: This study compares the antinociceptive and orexigenic activities of NPY and analogs after intracerebroventricular administration in mice. NPY had an antinociceptive action in the mouse writhing test which was not affected by prior treatment with naltrexone, yohimbine, idazoxan or reserpine. A detailed examination revealed that NPY (0.023-0.7 nmol), PYY (0.007-0.07 nmol), NPY2-36 (0.023-0.23 nmol) and the Y1 agonist [Leu31, Pro34]-NPY (0.07-0.7 nmol) all produced a dose-dependent and complete suppression of acetic acid-induced writhing. In contrast, the Y2 agonist, NPY13-36, had little or no antinociceptive effect. As shown by their ED50 values, the relative potency of the peptides was PYY > NPY2-36 > or = NPY > [Leu31, Pro34]-NPY > > NPY13-36, suggesting that a Y1 rather than a Y2 or Y3 receptor subtype was implicated in the antinociceptive action. Thereafter, all peptides were assessed for their effects on food intake. With respect to dose and peptide specificity, the hyperphagic effects of NPY and related peptides paralleled those on nociception, suggesting a common receptor mechanism. However, a purported NPY antagonist, [D-Trp32]-NPY, attenuated NPY's effect on feeding yet this same peptide elicited a dose-dependent inhibition of acetic acid-induced writhing, suggesting some molecular distinction between antinociception and stimulation of food intake.
    Brain Research 06/1996; 724(1):25-32. DOI:10.1016/0006-8993(96)00262-4 · 2.83 Impact Factor
  • R K Rao, Y Lopez, J Lai, P. J. M. Riviere, J L Junien, F Porreca
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    ABSTRACT: The effects of treatment with CCK receptor antagonists or administration of an antisense oligonucleotide to the gastrin receptor, on gastrin-I and cholecystokinin-8-induced acid secretion in mouse stomach were evaluated. Administration of gastrin-I (1 microM) or cholecystokinin-8 (30 nM) stimulated acid output at the rates of 2.6 +/- 0.27 and 1.0 +/- 0.21 microEq h-1, respectively. Gastrin-I-induced acid output was significantly blocked by pretreatment of stomachs with 3R[+]-N-[2,3-dihydro-1-methyl-2-oxo-5- phenyl-1H-1,4-benzodiazepin-3-yl]-N[3-methylphenyl[urea (L-365,260; 1 microM), but not by devazepide (L-364,718; 1 microM). Cholecystokinin-8-induced acid output, on the other hand, was sensitive to both L-365,260 (100 nM) and L-364,718 (100 nM). Administration of antisense, but not mismatch, oligonucleotide significantly reduced gastrin-induced acid output, while antisense oligonucleotide treatment had no effect on cholecystokinin-8-induced acid output. These results of antagonist and antisense oligonucleotide studies suggest that gastrin-I and cholecystokinin-8 may involve different receptor subtypes in stimulating gastric acid secretion in mice, and that antisense oligonucleotide administration may serve an useful tool in characterizing CCK/gastrin receptor subtypes.
    Neuroreport 12/1995; 6(17):2373-7. DOI:10.1097/00001756-199511270-00023 · 1.64 Impact Factor
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    ABSTRACT: The effect of fedotozine was evaluated in a model of colonic hypersensibility to balloon distension in anesthetized rats. Acetic acid (0.6%, intracolonically) significantly enhanced the hypotension reflex response to colonic distension (P < 0.05). At a noxious pain pressure (75 mm Hg), fedotozine ((+)-(-1R)-1-phenyl-1-[(3,4,5- trimethoxy)benzyloxymethyl]-N,N-dimethyl-n-propylamine) had no effect at 0.6 and 1 mg/kg i.v. in saline-treated rats and higher doses were required to produce antinociception (ED50 = 2.57 mg/kg i.v.). By contrast, fedotozine at 0.6 and 1 mg/kg i.v. displayed 38 and 54% antinociception (P < 0.05) respectively, in acetic acid-treated animals, leading to a decrease in its ED50 (1.15 mg/kg i.v.). Similar results were obtained with (+/-)-trans-N-methyl-N-[2-(pyrrolidinyl)-cyclohexyl]benzo[b]-thiophene- 4-acetamide (PD-117,302), a kappa-opioid receptor agonist, while the antinociceptive action of morphine and a kappa-opioid receptor agonist, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl)benzenacetamide ((+/-)-U-50,488H), was identical in control and acetic acid-treated animals. Nor-binaltorphimine, a selective kappa-opioid receptor antagonist, reversed the enhanced antinociceptive activity of fedotozine and PD-117,302. It is concluded that acetic acid induces colonic hypersensibility to painful mechanical stimuli and that some but not all kappa-opioid receptor ligands can have enhanced efficacy in this pathological situation.
    European Journal of Pharmacology 01/1995; 271(2-3):245-51. DOI:10.1016/0014-2999(94)90780-3 · 2.68 Impact Factor
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    ABSTRACT: Fedotozine has been shown to act on gastrointestinal sensitivity through peripheral κ-opioid receptors. The present study investigated the action of fedotozine and reference compounds, morphine and (±)-U-50, 488H, on duodenal pain in anesthetized rats. The noxious stimulus was produced by duodenal distension (100 mm Hg; 30 s). Fedotozine (1–5 mg/kg i.v.) produced a dose-dependent inhibition of the cardiovascular reflex induced by duodenal distension (ED50 = 1.87 mg/kg) but had no effect at doses up to 300 μg/rat by either intracerebroventricular (i.c.v.) or intrathecal routes (i.t.). The μ-opioid receptor agonist, morphine, was active by both i.v. (ED50 = 0.62 mg/kg) and i.c.v. routes (ED50 = 2.17 μg/rat) as was the κ-opioid receptor agonist, (±)-U-50, 488H (trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide) (ED50 = 0.25 mg/kg and 149 μg/rat for i.v. and i.c.v. routes, respectively). The selective κ-opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), abolished the response to fedotozine (5 mg/kg i.v.) and (±)-U-50, 488H (2 mg/kg i.v.) but not that to morphine (1 mg/kg i.v.). In contrast, naloxone (30 μg/kg i.v.) blocked the response to morphine (1 mg/kg i.v.) but not that to fedotozine (5 mg/kg i.v.) or (±)-U-50, 488H (2 mg/kg i.v.). It is concluded that the antinociceptive effects of fedotozine on duodenal pain are mediated by peripheral κ-opioid receptors.
    European Journal of Pharmacology 12/1994; 271(1-271):65-71. DOI:10.1016/0014-2999(94)90265-8 · 2.68 Impact Factor
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    ABSTRACT: The mechanisms underlying the antinociception induced by morphine or U-50,488H (trans-(+-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]- cyclohexyl)benzeneacetamide) against painful colonic distension were examined in anaesthetized rats. The respective ED50 values for morphine and U-50,488H were 0.34 and 0.35 mg/kg for the i.v. route, and 1.68 and 167 micrograms/rat for the i.c.v. route. Morphine was active by the intrathecal route (ED50 = 7.8 micrograms) whereas U-50,488H had no effect at doses up to 100 micrograms/rat. The morphine response was selectively antagonized by naloxone (30 micrograms/kg i.v.) whereas that of U-50,488H was blocked by nor-binaltorphimine (10 mg/kg s.c.). Bilateral vagotomy abolished the response to morphine at 0.35 mg/kg i.v. and reduced by 41.3% that to 1 mg/kg morphine, but had no effect on that to U-50,488H or i.c.v. morphine (10 micrograms/rat). It is concluded that peripheral mu- and kappa-opioid receptors may produce antinociception for colonic pain and that vagal integrity is required for mu-opioid but not kappa-opioid peripheral antinociception.
    European Journal of Pharmacology 06/1994; 257(1-2):181-7. DOI:10.1016/0014-2999(94)90710-2 · 2.68 Impact Factor
  • European Journal of Pharmacology 11/1990; 187(3):557-9. DOI:10.1016/0014-2999(90)90388-M · 2.68 Impact Factor
  • F. Porreca, S.C. Farmer, T.F. Burks, P.J.M. Rivière
    European Journal of Pharmacology 07/1990; 183(4):1207–1208. DOI:10.1016/0014-2999(90)94302-E · 2.68 Impact Factor

Publication Stats

379 Citations
73.14 Total Impact Points


  • 1990–1998
    • The University of Arizona
      • Department of Pharmacology
      Tucson, Arizona, United States