Quaternary naloxone blocks morphine analgesia in spinal but not intact rats

Milne, Richard; Coddington, Jan M.; Gamble, Gregory D.

doi:10.1016/0304-3940(90)90573-r

Cited by 46 publications

(31 citation statements)

References 15 publications

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“…The poor ability of thiorphan [14] and DALA [l 8] to cross the BBB supports the idea that they are acting at the sites of their administration. This last result is confirmed by the fact that subcuta neous pretreatment with naloxone prevents the gastric protective effects of intracerebroventricular injection of thiorphan and DALA, while naloxone methiodide, which does not reach the CNS [19], is ineffective. In contrast, both antagonists block the gastroprotective ef fects of the intraperitoneal administration of thiorphan and DALA.…”

Section: Discussionsupporting

confidence: 60%

Central and Peripheral Involvement of Endogenous Opioid Peptides in Gastric Protection in Stressed Rats

Scoto

Parenti²

1996

Pharmacology

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The effects of intraperitoneal and intracerebroventricular administration of the inhibitor of endopeptidase EC 24.11 (enkephalinase), thiorphan, and the synthetic enkephalin analogue [D-Ala²-Met⁵]enkephalinamide (DALA) were investigated in cold-restraint-stressed rats. Drugs were administered alone or after pretreatment with naloxone or naloxone methiodide given 20 min prior to the drugs. Thiorphan and DALA, administered centrally (4 µg i.c.v./rat) or peripherally (400 µg/kg), induced a significant gastric protection. Prior treatment with naloxone s.c. (1 mg/kg) inhibited the effect induced by i.e.v. or i.p. injections of thiorphan or DALA. In contrast, s.c. administration of naloxone methiodide (1 mg/ kg) did not affect the response induced by central administration of thiorphan or DALA, but was able to prevent that of thiorphan or DALA when they were administered i.p. These data strongly support the hypothesis of a central and peripheral involvement of endogenous opioid peptides in gastric protection in stressed rats.

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Section: Discussionsupporting

confidence: 60%

Central and Peripheral Involvement of Endogenous Opioid Peptides in Gastric Protection in Stressed Rats

Scoto

Parenti²

1996

Pharmacology

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“…However, since MOR is also expressed on various cells in peripheral tissues (11,(78)(79)(80), it may be speculated that there is a modulation of inflammation by peripheral MOR. In our study, the two selective MOR agonists, DALDA and DAMGO, and the MOR antagonist NM were selected for their inability to cross the blood-brain barrier (52)(53)(54). We therefore conclude that the protective effects of MOR during colon inflammation are probably mediated by peripheral and not central mechanisms.…”

Section: Discussionmentioning

confidence: 94%

“…These compounds were administered once daily by subcutaneous injection, starting either 4 days before (preventive mode) or 30 minutes after (treatment mode) colitis induction. To determine whether the beneficial effects of DALDA and DAMGO were due to selective activation of peripheral MOR, the MOR antagonist NM, which does not cross the blood-brain barrier (54), was given in some mice preventively and concomitantly 6 days before colitis induction at the dose of 2.5 mg/kg/d as described previously (55). Macroscopic, histological, and biological assessments of colitis were performed blindly by two investigators.…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory properties of the μ opioid receptor support its use in the treatment of colon inflammation

Philippe¹,

Dubuquoy²,

Groux³

et al. 2003

J. Clin. Invest.

148

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The physiologic role of the μ opioid receptor (MOR) in gut nociception, motility, and secretion is well established. To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4+ T cells in mice. This therapeutic effect was almost completely abolished by concomitant administration of the opioid antagonist naloxone. Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring 3 days after TNBS administration. The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD). These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD

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“…We assessed whether opioid peptides were able to affect LH secretion at a location outside of the bloodbrain barrier by using the quaternary derivative of NAL, naloxone methiodide (NALMI). Quaternary derivatives of NAL are inefficient in crossing the blood-brain barrier [45], yet are just as effective as NAL at stimulating LH release in the rat [46,47]. Since we found an effect of opioid blockade in young but not older male mice, we determined whether NAL could alter LH release at the level of the gonadotrope in the younger mice.…”

Section: Opioidergic Modulation Of N-methyl-d¿-aspartic-acidstimulatmentioning

confidence: 99%

Opioidergic Modulation of N-Methyl-D,L-Aspartic-Acid-Stimulated LH Release in Young Adult but not Older Male Mice

Miller

Gibson²

1994

Neuroendocrinology

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Among the neuromodulators of the GnRH neuronal system are the endogenous opioid peptides and the excitatory amino acids. Although the opioid antagonist naloxone (NAL) induces LH secretion in many species, there are no reports of an effect of NAL on LH release in mice. Our previous studies demonstrated that the excitatory amino acid analog N-methyl-D,L-aspartic acid (NMA) stimulates LH release in mice and suggested that NMA-induced LH release is mediated via afferents to GnRH neurons. In the current study, the role of the endogenous opioid system in the regulation of LH release in adult male mice was assessed by testing whether this system is a component of the NMA-stimulated LH response. NAL, its quaternary derivative NAL methiodide (which remains outside of the blood-brain barrier) and saline (SAL) were administered alone and in combination with NMA via intravenous catheters. Although neither opioid antagonist stimulated LH release when administered alone, each significantly potentiated the LH response to NMA in young adult (10- to 14-week-old) male mice (p < 0.01) but not in older (10- to 16-month-old) male mice. The equivalent action of the two ipioid blockers suggested an action outside of the blood-brain barrier. To determine whether opioid blockade altered pituitary sensitivity to GnRH, a dose response for exogenously administered GnRH was first determined, and low and high doses of GnRH were tested in combination with NAL or SAL. Neither treatment was effective in altering the LH response to GnRH, indicating that the action of the opioid antagonists was at a suprapituitary location. Ten- to 16-month-old male mice had significantly greater LH responses to NMA than 10- to 14-week-old male mice (p < 0.01). GnRH challenges indicated that the increased LH secretion to NMA seen in the older males was not due to an increased pituitary sensitivity to GnRH. These findings support the hypothesis that NMA stimulates opioidergic neurons which contribute an inhibitory influence on GnRH secretion at a central location outside of the blood-brain barrier, such as the median eminence, and that inhibitory influences on the GnRH neuronal system diminish with aging.

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Quaternary naloxone blocks morphine analgesia in spinal but not intact rats

Cited by 46 publications

References 15 publications

Central and Peripheral Involvement of Endogenous Opioid Peptides in Gastric Protection in Stressed Rats

Central and Peripheral Involvement of Endogenous Opioid Peptides in Gastric Protection in Stressed Rats

Anti-inflammatory properties of the μ opioid receptor support its use in the treatment of colon inflammation

Opioidergic Modulation of N-Methyl-D,L-Aspartic-Acid-Stimulated LH Release in Young Adult but not Older Male Mice

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