Targeting Pain-Suppressed Behaviors in Preclinical Assays of Pain and Analgesia: Effects of Morphine on Acetic Acid-Suppressed Feeding in C57BL/6J Mice

Stevenson, Glenn W.; Bilsky, Edward J.; Negus, S. Stevens

doi:10.1016/j.jpain.2006.01.447

Cited by 101 publications

(107 citation statements)

References 30 publications

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“…This study extended previous findings by using a higher intensity noxious stimulus (5.6% vs 1.8% lactic acid, see below), and despite use of this higher intensity stimulus, both ketoprofen and morphine retained efficacy to block acid-induced depression of ICSS. These results also agree with previous studies showing painrelated and analgesic-reversible depression of other behaviors including feeding (Kwilasz and Negus, 2012;Stevenson et al, 2006), locomotion (Cobos et al, 2012;Stevenson et al, 2009), burrowing (Andrews et al, 2012), and positively reinforced operant responding (Martin et al, 2004).…”

Section: Pain-related Depression Of Behaviorsupporting

confidence: 93%

“…The mechanisms of pain-related depression are not well understood. In preclinical studies, injury, disease, or treatment with experimental noxious stimuli can produce an analgesic-reversible depression of behaviors that include feeding (Kwilasz and Negus, 2012;Stevenson et al, 2006), locomotion (Cobos et al, 2012;Stevenson et al, 2009), burrowing (Andrews et al, 2012), and positively reinforced operant responding (Martin et al, 2004). For example, intracranial self-stimulation (ICSS) is an operant procedure in which subjects emit a learned response such as a lever press to earn pulses of electrical stimulation to brain reward areas (Carlezon and Chartoff, 2007;Olds and Milner, 1954).…”

Section: Introductionmentioning

confidence: 99%

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Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Leitl

Onvani

Bowers

et al. 2013

Neuropsychopharmacol

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Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This study tested the hypothesis that pain-related behavioral depression is mediated by activation of endogenous k-opioid systems and subsequent depression of mesolimbic dopamine release. Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle (for behavior studies of intracranial self-stimulation (ICSS)) or with cannulae for microdialysis measures of nucleus accumbens dopamine (NAc DA). Changes in ICSS and NAc DA were examined after treatment with a visceral noxious stimulus (intraperitoneal injection of dilute lactic acid) or an exogenous k-agonist (U69593). Additional studies examined the sensitivity of acid and U69593 effects to blockade by two analgesics (the nonsteroidal antiinflammatory drug ketoprofen and the m-opioid agonist morphine) or by the k-antagonist norbinaltorphimine (norBNI). The effects of acid were also examined on mRNA expression for prodynorphin (PDYN) and k-opioid receptors (KORs) in mesocorticolimbic brain regions. Both acid and U69593 depressed ICSS and extracellular levels of NAc DA. Pain-related acid effects were blocked by ketoprofen and morphine but not by norBNI. The U69593 effects were blocked by norBNI but not by ketoprofen, and were only attenuated by morphine. Acid did not significantly alter PDYN or KOR in NAc, but it produced a delayed increase in PDYN in prefrontal cortex. These results support a key role for the mesolimbic DA system, but a more nuanced role for endogenous k-opioid systems, in mediating acute pain-related behavioral depression in rats.

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Section: Pain-related Depression Of Behaviorsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Leitl

Onvani

Bowers

et al. 2013

Neuropsychopharmacol

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“…In the present study and a previous study (Negus et al, 2012a), the NSAID ketoprofen blocked acid-stimulated stretching and acid-induced depression of ICSS and feeding, and these data agree with the clinical efficacy of ketoprofen for the treatment of acute pain in animals (Flecknell, 2009) and humans (Sarzi-Puttini et al, 2010). Likewise, the -opioid receptor agonist and clinically effective analgesic morphine also blocked acid-stimulated stretching and acid-induced depression of ICSS in rats (Pereira Do Carmo et al, 2009;Negus et al, 2010b) and acid-induced depression of feeding in mice (Stevenson et al, 2006). Both NSAID and -opioid analgesics have also been shown to block other examples of pain-depressed behavior including acid-induced depression of locomotion and wheel running in mice Miller et al, 2011), laparotomy-induced depression of locomotion and food-maintained operant responding in rats (Martin et al, 2007), and depression of locomotion and wheel running induced by bilateral inflammation of the knee joints by complete Freund's adjuvant in rats (Matson et al, 2007;Cobos et al, 2012).…”

supporting

confidence: 53%

“…Accordingly, THC effects in assays of acid-stimulated stretching and aciddepressed ICSS were evaluated during chronic THC administration to test the hypothesis that repeated THC might produce selective tolerance to rate-decreasing effects and unmask antinociception in the assay of acid-depressed ICSS. Second, the effects of THC and CP55940 were evaluated in an assay of acid-induced depression of feeding (Stevenson et al, 2006). Feeding is reliably stimulated by THC and other cannabinoid agonists in the absence of pain (Williams et al, 1998;Miller et al, 2004;Jä rbe and DiPatrizio, 2005;Farrimond et al, 2011), suggesting that cannabinoids might be more effective in blocking acid-induced depression of feeding than acid-induced depression of ICSS.…”

Section: Introductionmentioning

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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“…While evoked responses often form the primary endpoint in animal models, randomized controlled trials in humans normally focus on endpoints relating to spontaneous pain, as well as other co-morbidities that impact on quality of life and general physical function . Recently, the measurement of nonevoked readouts for the assessment of analgesic efficacy against spontaneous pain in animals has been proposed (Stevenson et al, 2006;Matson et al, 2007;Andrews et al, 2011). Non-evoked readouts are proposed to improve the predictive validity of preclinical analgesia models, while evaluation of innate behaviours has been suggested to have the potential to improve the reliability of data Mogil, 2009).…”

Section: Introductionmentioning

confidence: 99%

Burrowing as a non‐reflex behavioural readout for analgesic action in a rat model of sub‐chronic knee joint inflammation

Rutten¹,

Schiene²,

Robens³

et al. 2013

European Journal of Pain

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Background: Innate responses against spontaneous pain are proposed to improve the predictive validity of preclinical analgesia models. Therefore, development and validation of novel readouts is necessary. To investigate whether innate rodent burrowing is a useful alternative behavioural readout for assessment of analgesic efficacy, a complete Freund's adjuvant (CFA)-induced model of sub-chronic inflammation was used to compare the effects of naproxen, ibuprofen and pregabalin in weight-bearing (WB), open-field (OF) and burrowing assays. Methods: Male Sprague Dawley rats were injected with 150 μL of CFA (2 mg/mL) into the knee (hind leg) 3 days before testing. Naproxen, ibuprofen and pregabalin were administered at different doses 30, 90 and 60 min, respectively, before testing. WB was determined using a rat incapacitance tester; horizontal distance moved and vertical rearings were recorded in an OF; and burrowing was measured by the weight of gravel remaining in a hollow tube after 60 min. Results: CFA-induced arthritis reduced WB, OF activity and burrowing. Naproxen, pregabalin and ibuprofen treatment normalized WB; however, horizontal OF activity was not improved by any treatment; rearing behaviour was moderately reinstated by ibuprofen (100 mg/kg). In burrowing, naproxen (100 mg/kg), ibuprofen (31.6 and 100 mg/kg) and pregabalin (10 mg/kg) reversed CFA-induced deficits. Conclusions: Burrowing performance is an alternative non-reflex readout relying on innate rodent behaviour that is affected by nociceptive behaviour and can be pharmacologically manipulated. The burrowing assay appears to be more sensitive than OF assays and is as sensitive as WB assays at distinguishing between analgesic doses and doses that impair locomotion.

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Targeting Pain-Suppressed Behaviors in Preclinical Assays of Pain and Analgesia: Effects of Morphine on Acetic Acid-Suppressed Feeding in C57BL/6J Mice

Cited by 101 publications

References 30 publications

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

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

Burrowing as a non‐reflex behavioural readout for analgesic action in a rat model of sub‐chronic knee joint inflammation

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Targeting Pain-Suppressed Behaviors in Preclinical Assays of Pain and Analgesia: Effects of Morphine on Acetic Acid-Suppressed Feeding in C57BL/6J Mice

Cited by 101 publications

References 30 publications

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

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

Burrowing as a non‐reflex behavioural readout for analgesic action in a rat model of sub‐chronic knee joint inflammation

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