Antinociceptive activity of intrathecal ketorolac is blocked by the receptor antagonist, nor-binaltorphimine

Uphouse, Laura A.; Welch, Sandra P.; Ward, C R; Ellis, Elliot F.; Embrey, James P.

doi:10.1016/0014-2999(93)90009-7

Cited by 29 publications

(11 citation statements)

References 8 publications

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“…When tested in animal models, ketorolac is an effective analgesic, antiinflammatory and antipyretic drug in adult rats (Rooks, 1990;Jett et al, 1999) and mice (Uphouse et al, 1993). In rats, its analgesic efficacy is 300 ± 500 times that of aspirin (Rooks et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…Its analgesic efficacy is comparable to opiates in strabismus surgery (Shende and Das, 1999), bladder surgery (Gonzalez and Smith, 1998), tonsillectomy (Mather and Peutrell, 1995), and dental surgery (Purday et al, 1996). There is no reported experience with its use in human neonates.When tested in animal models, ketorolac is an effective analgesic, antiinflammatory and antipyretic drug in adult rats (Rooks, 1990;Jett et al, 1999) and mice (Uphouse et al, 1993). In rats, its analgesic efficacy is 300 ± 500 times that of aspirin (Rooks et al, 1985).…”

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Analgesic efficacy of ketorolac and morphine in neonatal rats

Gupta

Cheng

Wang

et al. 2001

Pharmacology Biochemistry and Behavior

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Ketorolac is a potent nonsteroidal antiinflammatory drug (NSAID). In adult humans and animals, its analgesic efficacy can be comparable to opiates. However, it has not been studied in neonatal animals. We conducted a blinded, controlled study comparing the effects of ketorolac and morphine in neonatal rats using the formalin model. Animals were given intraperitoneal (ip) injections of ketorolac or morphine at 3 or 21 days of age. Ketorolac had an analgesic and antiinflammatory effect in 21-day-old pups, but not in the 3-day-olds. Morphine had a significant analgesic, but no antiinflammatory effect at both ages. These results indicate that ketorolac is an effective analgesic agent in preweaning, but not neonatal rats. Opiates may be more appropriate analgesics in neonates. D 2001 Elsevier Science Inc. All rights reserved.Keywords: Ketorolac; Morphine; Neonatal rats; Formalin BackgroundKetorolac is one of the most potent nonsteroidal antiinflammatory (NSAID) drugs available for clinical use. It can be administered orally, parenterally, and topically (for ocular inflammation). Its effects are mainly peripheral due to nonselective inhibition of cyclo-oxygenase and subsequent reduction of prostaglandin production (especially prostaglandin E2) (Zhang et al., 1997). Data from animal studies also suggest that ketorolac may have a central modulatory effect on opioid pharmacology (Maves et al., 1994).In human adults, ketorolac has been extensively evaluated in the relief of postoperative pain and other acute pain states. It has similar analgesic efficacy as morphine and meperidine in relieving postoperative pain, and is tolerated well with few side effects (renal, gastrointestinal, platelet function) (Gillis and Brogden, 1997). In the emergency department, in patients with renal colic (Larkin et al., 1999), migraine headache, musculoskeletal pain, or sickle crisis, ketorolac reduces pain as effectively as opiates (Gillis and Brogden, 1997). Ketorolac also has a synergistic effect with morphine and fentanyl and reduces the need for opiates in the postoperative period in both human adults (Picard et al., 1997) and children (Chiaretti et al., 1997). The combination of ketorolac and opiates allows the use of subtherapeutic doses of both drugs and reduction in their side effects. In the pediatric population, ketorolac has mostly been used in children over the age of 2 years. Its analgesic efficacy is comparable to opiates in strabismus surgery (Shende and Das, 1999), bladder surgery (Gonzalez and Smith, 1998), tonsillectomy (Mather and Peutrell, 1995), and dental surgery (Purday et al., 1996). There is no reported experience with its use in human neonates.When tested in animal models, ketorolac is an effective analgesic, antiinflammatory and antipyretic drug in adult rats (Rooks, 1990;Jett et al., 1999) and mice (Uphouse et al., 1993). In rats, its analgesic efficacy is 300 ± 500 times that of aspirin (Rooks et al., 1985). In adult rat models of inflammatory pain using intraarticular injection of uric acid, ketorolac i...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Analgesic efficacy of ketorolac and morphine in neonatal rats

Gupta

Cheng

Wang

et al. 2001

Pharmacology Biochemistry and Behavior

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“…However, studies using compounds with relative preferences for ␦ and receptors have suggested that these other two opiate receptor subtypes also might play significant roles in the analgesic responses induced by morphine-like drugs (22)(23)(24)(25)(26). The extent to which each of the three opiate receptor subtype gene products might participate in different features of opiate-or morphineinduced analgesia thus has remained unclear.…”

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Opiate receptor knockout mice define μ receptor roles in endogenous nociceptive responses and morphine-induced analgesia

Sora

Takahashi

Funada

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

476

335

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Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. , ␦, and opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in drug-free and morphine-treated states have not been clear, however. We produced homologous, recombinant , opiate receptor, heterozygous and homozygous knockout animals that displayed Ϸ54% and 0% of wild-type levels of receptor expression, respectively. These mice expressed receptors and ␦ receptors at near wild-type levels. Untreated knockout mice displayed shorter latencies on tail f lick and hot plate tests for spinal and supraspinal nociceptive responses than wild-type mice. These findings support a significant role for endogenous opioid-peptide interactions with opiate receptors in normal nociceptive processing. Morphine failed to significantly reduce nociceptive responses in hot plate or tail f lick tests of homozygous receptor knockout mice, and heterozygote mice displayed right and downward shifts in morphine analgesia dose-effect relationships. These results implicate endogenous opioidpeptide actions at opiate receptors in several tests of nociceptive responsiveness and support receptor mediation of morphine-induced analgesia in tests of spinal and supraspinal analgesia.Morphine acts at seven transmembrane domain, G proteinlinked receptor products of genes encoding , , and ␦ opiate receptor subtypes (1-9). Each of these genes is expressed in neurons in several neuronal circuits implicated in nociception (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).receptor mediation of much morphine-induced analgesia has been postulated (21, 22). However, studies using compounds with relative preferences for ␦ and receptors have suggested that these other two opiate receptor subtypes also might play significant roles in the analgesic responses induced by morphine-like drugs (22-26). The extent to which each of the three opiate receptor subtype gene products might participate in different features of opiate-or morphineinduced analgesia thus has remained unclear. Elucidation of the selective analgesic contributions of each opiate receptor subtype is of substantial potential importance for developing improved analgesic medications with minimal undesirable effects.Expression of endogenous opioid-peptide agonists, especially those derived from the preproenkephalin and preprodynorphin genes, in circuits associated with pain perception suggests that opioid-peptide interactions with opiate receptors could be well positioned to modulate nociceptive responses in the absence of exogenously administered opiate drugs (10,12,14,(27)(28)(29)(30)(31)(32). Studies of pain responses in animals and humans treated with opiate antagonists, however, have documented modifications in nociception in some but not all studies (33,34). These results also have left uncertainty about the power of endogenous opioid-peptide interactions with ...

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“…IVRB with Ketorolac is reported to be especially useful for the treatment of hyperalgesia, joint pain, and edema [18]. Ketorolac decreases the sensitization associated with prostaglandin E2-mediated bradykinin hyperalgesia, tissue ischemia, vasodilation, and k-opioid receptors, by inhibiting thromboxane [18,19]. …”

Section: Discussionmentioning

confidence: 99%