Predictive validity of animal pain models? A comparison of the pharmacokinetic–pharmacodynamic relationship for pain drugs in rats and humans

Whiteside, Garth T.; Adedoyin, Adedayo; Leventhal, Liza

doi:10.1016/j.neuropharm.2008.01.001

Cited by 124 publications

(75 citation statements)

References 66 publications

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“…Efforts to improve pain medications include the search for new pharmacological targets as well as development of new strategies to minimize unwanted effects of existing medications. Development of improved preclinical assays may also contribute to analgesic development, because existing assays have been unreliable in predicting clinical drug effects Whiteside et al, 2008;Mogil, 2009). …”

Section: Introductionmentioning

confidence: 99%

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Altarifi

Rice

Negus

2014

J Pharmacol Exp Ther

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Pain is associated with stimulation of some behaviors and depression of others, and m-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male SpragueDawley rats to compare antinociception profiles for six m-agonists that varied in efficacy at m-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All m-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lowerefficacy agonists displayed similar potency across assays. All m-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy m-agonist nalbuphine, but not the high-efficacy m-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective m-opioid analgesics and reveal distinctions between opioids based on efficacy at the m-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.

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Section: Introductionmentioning

confidence: 99%

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Altarifi

Rice

Negus

2014

J Pharmacol Exp Ther

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“…The anticipated human efficacy profile is often based on data from preclinical models. To facilitate rational drug candidate selection, it is imperative to both characterize and quantify differences between the compounds and to quantify similarities and differences for the relevant efficacy endpoints between species to facilitate translation of preclinical findings to clinical efficacy (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

et al. 2011

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“…Preclinical assays of pain and analgesia play a critical role in analgesic drug development, but there is a growing appreciation that drug effects in conventional preclinical assays of pain-stimulated behavior are often poor predictors of clinical analgesic efficacy in humans (Blackburn-Munro, 2004;Negus et al, 2006;Whiteside et al, 2008;Mogil, 2009). Results with THC and CP55940 have illustrated this discordance insofar as cannabinoid agonists produce robust and reliable antinociception in most assays of acute pain-stimulated behavior but little or no analgesia against acute pain in humans (Rice, 2006;Karst et al, 2010;Kraft, 2012).…”

mentioning

confidence: 99%

Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

Kwilasz

Negus

2012

J Pharmacol Exp Ther

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Cannabinoid receptor agonists produce reliable antinociception in most preclinical pain assays but have inconsistent analgesic efficacy in humans. This disparity suggests that conventional preclinical assays of nociception are not sufficient for the prediction of cannabinoid effects related to clinical analgesia. To extend the range of preclinical cannabinoid assessment, this study compared the effects of the marijuana constituent and low-efficacy cannabinoid agonist ⌬ 9 -tetrahydrocannabinol (THC) and the high-efficacy synthetic cannabinoid agonist 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (CP55940) in assays of pain-stimulated and paindepressed behavior. Intraperitoneal injection of dilute lactic acid (1.8% in 1 ml/kg) stimulated a stretching response or depressed intracranial self-stimulation (ICSS) in separate groups of male Sprague-Dawley rats. THC (0.1-10 mg/kg) and CP55940 (0.0032-0.32 mg/kg) dose-dependently blocked acidstimulated stretching but only exacerbated acid-induced depression of ICSS at doses that also decreased control ICSS in the absence of a noxious stimulus. Repeated THC produced tolerance to sedative rate-decreasing effects of THC on control ICSS in the absence of the noxious stimulus but failed to unmask antinociception in the presence of the noxious stimulus. THC and CP55940 also failed to block pain-related depression of feeding in rats, although THC did attenuate satiationrelated depression of feeding. In contrast to the effects of the cannabinoid agonists, the clinically effective analgesic and nonsteroidal anti-inflammatory drug ketoprofen (1 mg/kg) blocked acid-stimulated stretching and acid-induced depression of both ICSS and feeding. The poor efficacy of THC and CP55940 to block acute pain-related depression of behavior in rats agrees with the poor efficacy of cannabinoids to treat acute pain in humans.

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Predictive validity of animal pain models? A comparison of the pharmacokinetic–pharmacodynamic relationship for pain drugs in rats and humans

Cited by 124 publications

References 66 publications

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

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Predictive validity of animal pain models? A comparison of the pharmacokinetic–pharmacodynamic relationship for pain drugs in rats and humans

Cited by 124 publications

References 66 publications

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Pharmacokinetic-Pharmacodynamic Modeling of the Inhibitory Effects of Naproxen on the Time-Courses of Inflammatory Pain, Fever, and the Ex Vivo Synthesis of TXB2 and PGE2 in Rats

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

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Dissociable Effects of the Cannabinoid Receptor Agonists Δ⁹-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats