Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats

doi:10.1016/S0028-3908(01)00173-3

Neuropharmacology

Volume 42, Issue 2, February 2002, Pages 253-261

https://doi.org/10.1016/S0028-3908(01)00173-3 Get rights and content

Abstract

The effects of the peripherally restricted opioid agonist loperamide were compared to those of morphine in the formalin test in rats. Both loperamide and morphine were efficacious in producing antihyperalgesia after both subcutaneous and intracisternal administration. The antihyperalgesic effects of peripherally administered loperamide and morphine were antagonized by both naloxone and its quaternary derivative naloxone methiodide. The effects of intracisternally administered loperamide and morphine were antagonized by naloxone SC. However, quaternary naloxone SC did not block the effects of intracisternally administered loperamide, and, quaternary naloxone blocked intracisternally morphine only at a dose approximately 10-fold higher than that required to block peripherally administered morphine. In addition, approximately 10-fold higher doses of naloxone administered SC were required to antagonize loperamide compared to doses required to antagonize morphine when the agonists were administered subcutaneously, suggesting that the effects of loperamide might be mediated by opioid receptors different from those which mediated the effects of morphine. However, neither the κ-receptor selective antagonist nor-binaltorphimine nor the δ-receptor selective antagonist naltrindole blocked the effects of either opioid agonist. The present results are consistent with the interpretation that the antihyperalgesic effects of opioid agonists can have both a peripheral and a central component of action, and that the peripheral component of action is sufficient to produce antihyperalgesia in the formalin test after peripheral administration. The present results provide further evidence that peripherally restricted opioid agonists might provide clinically useful treatment of some pain states, in particular pain states that might involve sensitization of peripheral nociceptors.

Section snippets

Subjects

Male Sprague–Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) weighing 180–220 g were used. Rats were housed up to eight per cage in a large colony room, and provided with food and water ad libitum with a 12-h light/dark cycle. Each animal was used only once. All procedures were approved by the Eli Lilly Institutional Animal Care and Use Committee.

Formalin test

The methods used were based on the automated method of Jett and Michelson (1996) as modified by Shannon and Lutz (2000). All testing took place

Subcutaneous administration of loperamide and morphine

In animals administered vehicle SC 30 min before formalin, there was an initial peak in the number of events during the first 5-min block after formalin, followed by a decrease in the number of events in the second 5-min block, and subsequently an increase again in blocks 3–9 (Fig. 1, open circles). When loperamide was administered SC 30 min before formalin, it produced a dose- and time-dependent analgesic effect in the formalin test in rats (Fig. 1). Loperamide (1.0–10 mg/kg SC) was

Discussion

The major finding of the present studies was that the opioid agonists loperamide and morphine produced antihyperalgesia after subcutaneous administration in the formalin test in rats, most likely by acting at peripheral opioid receptors. Loperamide, which does not penetrate into the brain in appreciable amounts (Heykants et al., 1974, Wuster and Herz, 1978, Schinkel et al., 1996), was efficacious in reducing formalin-induced nocifensive behaviors. Moreover, the quaternary opioid antagonist

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Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats

Abstract

Section snippets

Subjects

Formalin test

Subcutaneous administration of loperamide and morphine

Discussion

Journal of Biological Chemistry

Life Sciences

Pain

Neuropsychopharmacology

Pain

European Journal of Pharmacology

Pain

European Journal of Pharmacology

Life Sciences

Kappa opioid antagonist effects of systemically administered nor-binaltorphimine in a thermal antinociception assay in rhesus monkeys

Journal of Pharmacology and Experimental Therapeutics

Discriminative stimulus effects of BW373U86: a nonpeptide ligand with selectivity for delta opioid receptors

Journal of Pharmacology and Experimental Therapeutics

Loperamide (ADL-1294), an opioid antihyperalgesic agent with peripheral selectivity

Journal of Pharmacology and Experimental Therapeutics

Loperamide (R 18 553), a novel type of antidiarrheal agent

Arzneim-Forsch/Drug Research

Nor-binaltorphimine: an ultra-long acting kappa-opioid antagonist in pigeons

Behavioural Pharmacology