A Translational Study of the Effects of Ketamine and Pregabalin on Temporal Summation of Experimental Pain

Arendt-Nielsen, Lars; Mansikka, Heikki; Staahl, Camilla; Rees, H.; Tan, Keith; Smart, Trevor S.; Monhemius, R.; Suzuki, Rie; Drewes, Asbjørn Mohr

doi:10.1097/aap.0b013e31822b0db0

Cited by 30 publications

(22 citation statements)

References 31 publications

(29 reference statements)

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“…Temporal summation QST is a well-recognized mechanism-based evaluation technique for musculoskeletal pain in humans [14], [20], [21], [23]. Hence, evoked TS has considerable potential for effective translational research [43]. A further advantage of investigation into central sensitization is that this phenomenon is potentially reversible.…”

Section: Discussionmentioning

confidence: 99%

Evoked Temporal Summation in Cats to Highlight Central Sensitization Related to Osteoarthritis-Associated Chronic Pain: A Preliminary Study

Guillot

Taylor²,

Rialland

et al. 2014

PLoS ONE

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In cats, osteoarthritis causes significant chronic pain. Chronicity of pain is associated with changes in the central nervous system related to central sensitization, which have to be quantified. Our objectives were 1) to develop a quantitative sensory testing device in cats for applying repetitive mechanical stimuli that would evoke temporal summation; 2) to determine the sensitivity of this test to osteoarthritis-associated pain, and 3) to examine the possible correlation between the quantitative sensory testing and assessment using other pain evaluation methods. We hypothesized that mechanical sub-threshold repetitive stimuli would evoke temporal summation, and that cats with osteoarthritis would show a faster response. A blinded longitudinal study was performed in 4 non-osteoarthritis cats and 10 cats with naturally occurring osteoarthritis. Quantification of chronic osteoarthritis pain-related disability was performed over a two week period using peak vertical force kinetic measurement, motor activity intensity assessment and von Frey anesthesiometer-induced paw withdrawal threshold testing. The cats afflicted with osteoarthritis demonstrated characteristic findings consistent with osteoarthritis-associated chronic pain. After a 14-day acclimation period, repetitive mechanical sub-threshold stimuli were applied using a purpose-developed device. Four stimulation profiles of predetermined intensity, duration and time interval were applied randomly four times during a four-day period. The stimulation profiles were different (P<0.001): the higher the intensity of the stimulus, the sooner it produced a consistent painful response. The cats afflicted with osteoarthritis responded more rapidly than cats osteoarthritis free (P = 0.019). There was a positive correlation between the von Frey anesthesiometer-induced paw withdrawal threshold and the response to stimulation profiles #2 (2N/0.4 Hz) and #4 (2N/0.4 Hz): Rhos = 0.64 (P = 0.01) and 0.63 (P = 0.02) respectively. This study is the first report of mechanical temporal summation in awake cats. Our results suggest that central sensitization develops in cats with naturally occurring osteoarthritis, providing an opportunity to improve translational research in osteoarthritis-associated chronic pain.

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Section: Discussionmentioning

confidence: 99%

Evoked Temporal Summation in Cats to Highlight Central Sensitization Related to Osteoarthritis-Associated Chronic Pain: A Preliminary Study

Guillot

Taylor²,

Rialland

et al. 2014

PLoS ONE

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“…Windup is another electrophysiologic measure that is affected by drugs that are used to treat neuropathic pain (Arendt-Nielsen et al, 2011). In the animal assay of windup, a train of 16 electrical stimuli (2 ms, 0.5 Hz, 2 mA) was delivered transcutaneously to the hind paw to activate C-fiber–mediated windup activity of the wide-dynamic range neurons in the spinal dorsal horn of naive rats, and the effect of LP-935509 on the windup activity was then examined.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Kostich

Hamman²,

Li³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

127

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To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

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“…Second, clinical pain is multidimensional (ie, affective-motivational, sensory-discriminative) and evidence suggests different dimensions may reflect diverse underlying mechanisms 90–92. The evidence also suggests that treatments may preferentially improve some dimensions over others 21,93,94. Reductions in measures of pain sensitivity are associated with improvements in movement-related pain to a greater extent than improvements in spontaneous pain 21.…”

Section: Discussionmentioning

confidence: 99%

Effect of a single session of muscle-biased therapy on pain sensitivity: a systematic review and meta-analysis of randomized controlled trials

Alappattu

Coronado

Horn

et al. 2013

JPR

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BackgroundMuscle-biased therapies (MBT) are commonly used to treat pain, yet several reviews suggest evidence for the clinical effectiveness of these therapies is lacking. Inadequate treatment parameters have been suggested to account for inconsistent effects across studies. Pain sensitivity may serve as an intermediate physiologic endpoint helping to establish optimal MBT treatment parameters. The purpose of this review was to summarize the current literature investigating the short-term effect of a single dose of MBT on pain sensitivity in both healthy and clinical populations, with particular attention to specific MBT parameters of intensity and duration.MethodsA systematic search for articles meeting our prespecified criteria was conducted using Cumulative Index to Nursing and Allied Health Literature (CINAHL) and MEDLINE from the inception of each database until July 2012, in accordance with guidelines from the Preferred Reporting Items for Systematic reviews and Meta-Analysis. Relevant characteristics from studies included type, intensity, and duration of MBT and whether short-term changes in pain sensitivity and clinical pain were noted with MBT application. Study results were pooled using a random-effects model to estimate the overall effect size of a single dose of MBT on pain sensitivity as well as the effect of MBT, dependent on comparison group and population type.ResultsReports from 24 randomized controlled trials (23 articles) were included, representing 36 MBT treatment arms and 29 comparative groups, where 10 groups received active agents, 11 received sham/inert treatments, and eight received no treatment. MBT demonstrated a favorable and consistent ability to modulate pain sensitivity. Short-term modulation of pain sensitivity was associated with short-term beneficial effects on clinical pain. Intensity of MBT, but not duration, was linked with change in pain sensitivity. A meta-analysis was conducted on 17 studies that assessed the effect of MBT on pressure pain thresholds. The results suggest that MBT had a favorable effect on pressure pain thresholds when compared with no-treatment and sham/inert groups, and effects comparable with those of other active treatments.ConclusionThe evidence supports the use of pain sensitivity measures by future research to help elucidate optimal therapeutic parameters for MBT as an intermediate physiologic marker.

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A Translational Study of the Effects of Ketamine and Pregabalin on Temporal Summation of Experimental Pain

Abstract: It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.

Cited by 30 publications

References 31 publications

Evoked Temporal Summation in Cats to Highlight Central Sensitization Related to Osteoarthritis-Associated Chronic Pain: A Preliminary Study

Evoked Temporal Summation in Cats to Highlight Central Sensitization Related to Osteoarthritis-Associated Chronic Pain: A Preliminary Study

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Effect of a single session of muscle-biased therapy on pain sensitivity: a systematic review and meta-analysis of randomized controlled trials

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