Nonmammalian Models for the Study of Pain

Stevens, Craig W.

doi:10.1007/978-1-59745-285-4_37

Cited by 10 publications

(9 citation statements)

References 128 publications

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“…Specifically, the antinociceptive potency of mu -, delta -, and kappa - selective opioid agonists after systemic (Stevens et al, 1994), intraspinal (Stevens, 1996), or intracerebroventricular (Stevens and Rothe, 1997) administration in amphibians was highly correlated to that observed in mammals and to the relative potency of opioid analgesics in human clinical studies. These results, and other studies over the last two decades, validated the amphibian model as an alternative or adjunct model for pain and analgesia research (Stevens, 2008). However, behavioral studies in Rana pipiens suggested that the selectivity of opioid ligands for the different types of opioid receptors was different in mammalian and non-mammalian species.…”

Section: Introductionsupporting

confidence: 68%

A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function

Brasel

Sawyer

Stevens

2008

European Journal of Pharmacology

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This study presents a direct comparison of the ligand binding and signaling profiles of a mammalian and non-mammalian mu opioid receptor. Opioid ligand binding and agonist potencies were determined for an amphibian (Rana pipiens) mu opioid receptor (rpMOR) and the human mu opioid receptor (hMOR) in transfected, intact Chinese hamster ovary (CHO) cells. Identical conditions were employed such that statistically meaningful differences between the two receptors could be determined. Identifying these differences is an important first step in understanding how evolutionary changes affect ligand binding and signaling in vertebrate opioid receptors. As expected, the rank of opioid ligand affinity for rpMOR and hMOR were consistent with the ligands' previously characterized type-selectivity. However, most of the opioid ligands tested had significant differences in affinity for rpMOR and hMOR. For example, the mu-selective agonist, DAMGO ([D-Ala 2 , NMe-Phe 4 , Gly 5 -ol]-enkephalin), had a 10.9-fold greater affinity for hMOR (K i = 268 nM) than rpMOR (K i = 2,914 nM). In addition, differences in signaling between these receptors were found by measuring inhibition of cAMP accumulation by morphine or DAMGO. DAMGO was significantly more potent (13.6-fold) in CHO cells expressing hMOR versus those expressing rpMOR. In addition, a significantly greater maximal inhibition was elicited by both opioid agonists in cells expressing hMOR. In summary, this study supports an ongoing effort to better understand how vertebrate evolution has shaped opioid receptor properties and function.

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Section: Introductionsupporting

confidence: 68%

A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function

Brasel

Sawyer

Stevens

2008

European Journal of Pharmacology

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“…Insofar as we know, there are no published dose–response relations for the antinociceptive effects of morphine in fish. The only dose–response relations for morphine in a lower vertebrate used the acetic acid test on the skin of frogs (Stevens & Rothe, 1997; Stevens, 2008a,b) and reported ED 50 values of 65 mg/kg when given subcutaneous but only 0.05 mg/kg when given intraspinally, about one‐half the value for rodents. However, there are some reports using one or two doses of morphine that suggest its effectiveness as an antinociceptive drug in fish.…”

Section: Discussionmentioning

confidence: 99%

The dose–response relation for the antinociceptive effect of morphine in a fish, rainbow trout

Jones¹,

Kamunde²,

Lemke³

et al. 2012

Vet Pharm & Therapeutics

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There have been suggestions that analgesics be used by fish researchers. But in the absence of dose-response data for morphine, this suggestion seems imprudent. The purpose of the present study was to develop a dose-response relationship in fish using six doses of morphine. The response (movement of the fins or tail) to a noxious stimulus (electrical shock to the face region) was monitored before and after a dose of morphine intraperitoneally (i.p.). The i.p. dose of morphine ED(50) in rainbow trout was 6.7 ± 0.8 mg/kg (n = 12 at each dose). The plasma morphine concentration EC(50) was 4.1 ± 1.5 mg/L. In a second experiment, rainbow trout tested with equal amounts of morphine and naloxone (30 mg/kg) showed that the antinociceptive effect of morphine was blocked by naloxone. It has been suggested that stress-induced analgesia has been a confounding factor in some fish studies. However, plasma cortisol levels in our study indicated that stress was not a confounding factor in the present experiments. The ED(50) for morphine in fish was higher than that reported for humans or other mammals. Our observation showing a dose-response relation for morphine using a noxious stimulus supports arguments for its effectiveness as an antinociceptive drug in fish.

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“…These data established the amphibian model as a robust and predictive adjunct model for the testing of opioid analgesics (83–86). Other studies in amphibians used the acetic acid test to demonstrate that regional hypothermia produces antinociceptive effects that is mediated in part by endogenous opioid peptides (87).…”

Section: Opioid Receptors In Non-mammalian Vertebratesmentioning

confidence: 95%

The evolution of vertebrate opioid receptors

Stevens¹

2009

Front Biosci

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The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely-related proteins belonging to the large superfamily of G-protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This review presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptors arose by gene duplication, that there is a vector of opioid receptor divergence, and that MOR shows evidence of rapid evolution.

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Nonmammalian Models for the Study of Pain

Cited by 10 publications

References 128 publications

A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function

A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function

The dose–response relation for the antinociceptive effect of morphine in a fish, rainbow trout

The evolution of vertebrate opioid receptors

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