Central sensitization refers to enhanced excitability of dorsal horn neurons and is characterized by increased spontaneous activity, enlarged receptive field (RF) areas, and an increase in responses evoked by large and small caliber primary afferent fibers. Sensitization of dorsal horn neurons often occurs following tissue injury and inflammation and is believed to contribute to hyperalgesia. Windup refers to the progressive increase in the magnitude of C-fiber evoked responses of dorsal horn neurons produced by repetitive activation of C-fibers. In the present study, we tested the hypothesis that windup leads to central sensitization. Recordings were made from rat nociceptive dorsal horn neurons classed as wide dynamic range. Windup was produced by conditioning stimuli in a train of 12 electrical pulses (0.5 ms duration) applied to the RF at intensities three times the threshold for excitation of C-fibers and at a frequency of 0.5 Hz. Single electrical stimuli applied outside the RF never evoked responses except when delivered following conditioning stimulation inside the RF, indicating an expansion of the RF following windup. C-Fiber conditioning stimuli applied outside the RF also increased the response evoked by a single stimulus and increased the total number of spikes evoked by a train of electrical stimuli delivered inside the RF. Although both A- and C-fibers were activated, conditioning stimuli did not alter subsequent responses evoked by stimulation of A-fibers. Enhanced responsivity to C-fiber input following windup produced by stimulation inside the RF at a frequency of 0.5 Hz could be maintained for approximately 100 s by stimuli delivered at 0.1 Hz, a frequency that itself cannot produce windup. It is concluded that neuronal events leading to windup also produce some of the classical characteristics of central sensitization including expansion of RFs and enhanced responses to C- but not A-fiber stimulation. Thus, windup may be a useful tool to study mechanisms underlying certain characteristics of central sensitization related to C-fiber activity.
"The heterogeneous first order autoregressive structure may be reasonable due to the equally spaced time points, but the quality of the fit and the assumptions made could not be tested or checked. The complexity of this model and the potential for misleading estimates of treatment means and standard errors ,  meant that it was unwise to make inferences from the model. ANCOVA was preferred to the less sophisticated, and potentially biased, methods of correcting for baseline such as percent change and subtraction as it uses the data to estimate the appropriate correction to minimize the residual variability , . "
[Show abstract][Hide abstract] ABSTRACT: Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.
PLoS ONE 08/2014; 9(8):e106108. DOI:10.1371/journal.pone.0106108 · 3.23 Impact Factor
"Intensity-dependent neuromodulation for neuropathic pain responses to the electrical test stimuli applied through a pair of fine stimulating electrodes inserted subcutaneously into the receptive field (Fig. 1A). The WDR neuronal response to a suprathreshold electrical stimulus consists of an early A-fibre component (0–75 ms) and a later C-fibre component (75–500 ms) (Li et al., 1999; Guan et al., 2010a) (Fig. 1C). The stimulus-response (S-R) functions of the C-components to graded intracutaneous electrical stimuli (0.1–10 mA, 2.0 ms, 15-s interval) were determined first. "
[Show abstract][Hide abstract] ABSTRACT: Spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) are thought to reduce pain by activating a sufficient number of large myelinated (Aβ) fibres, which in turn initiate spinal segmental mechanisms of analgesia. However, the volume of neuronal activity and how this activity is associated with different treatment targets is unclear under neuropathic pain conditions.
We sought to delineate the intensity-dependent mechanisms of SCS and PNS analgesia by in vivo extracellular recordings from spinal wide-dynamic range neurons in nerve-injured rats. To mimic therapeutic SCS and PNS, we used bipolar needle electrodes and platinum hook electrodes to stimulate the dorsal column and the tibial nerve, respectively. Compound action potentials were recorded to calibrate the amplitude of conditioning stimulation required to activate A-fibres and thus titrate the volume of activation.
Dorsal column stimulation (50 Hz, five intensities) inhibited the windup (a short form of neuronal sensitization) and the C-component response of wide-dynamic range neurons to graded intracutaneous electrical stimuli in an intensity-dependent manner. Tibial nerve stimulation (50 Hz, three intensities) also suppressed the windup in an intensity-dependent fashion but did not affect the acute C-component response.
SCS and PNS may offer similar inhibition of short-term neuronal sensitization. However, only SCS attenuates spinal transmission of acute noxious inputs under neuropathic pain conditions. Our findings begin to differentiate peripheral from spinal-targeted neuromodulation therapies and may help to select the best stimulation target and optimum therapeutic intensity for pain treatment.
European journal of pain (London, England) 08/2014; 18(7). DOI:10.1002/j.1532-2149.2013.00443.x · 2.93 Impact Factor
"In previous studies using repetitive nociceptive stimuli, FM patients not only showed abnormal WU but also prolonged WU- aftersensations (WU-AS) (i.e. slower WU decay) –, both of which reflect central sensitization –. Whereas in previous studies of FM patients WU-AS were highly predictive of pain intensity , WU itself did not significantly contribute to estimates of these patients’ clinical pain , . This lack of correlations between clinical pain intensity and WU was thought to be related to insufficient statistical power as well as ceiling or floor effects . "
[Show abstract][Hide abstract] ABSTRACT: In healthy individuals slow temporal summation of pain or wind-up (WU) can be evoked by repetitive heat-pulses at frequencies of ≥.33 Hz. Previous WU studies have used various stimulus frequencies and intensities to characterize central sensitization of human subjects including fibromyalgia (FM) patients. However, many trials demonstrated considerable WU-variability including zero WU or even wind-down (WD) at stimulus intensities sufficient for activating C-nociceptors. Additionally, few WU-protocols have controlled for contributions of individual pain sensitivity to WU-magnitude, which is critical for WU-comparisons. We hypothesized that integration of 3 different WU-trains into a single WU-response function (WU-RF) would not only control for individuals' pain sensitivity but also better characterize their central pain responding including WU and WD.
33 normal controls (NC) and 38 FM patients participated in a study of heat-WU. We systematically varied stimulus intensities of.4 Hz heat-pulse trains applied to the hands. Pain summation was calculated as difference scores of 1st and 5th heat-pulse ratings. WU-difference (WU-Δ) scores related to 3 heat-pulse trains (44°C, 46°C, 48°C) were integrated into WU-response functions whose slopes were used to assess group differences in central pain sensitivity. WU-aftersensations (WU-AS) at 15 s and 30 s were used to predict clinical FM pain intensity.
WU-Δ scores linearly accelerated with increasing stimulus intensity (p<.001) in both groups of subjects (FM>NC) from WD to WU. Slope of WU-RF, which is representative of central pain sensitivity, was significantly steeper in FM patients than NC (p<.003). WU-AS predicted clinical FM pain intensity (Pearson's r = .4; p<.04).
Compared to single WU series, WU-RFs integrate individuals' pain sensitivity as well as WU and WD. Slope of WU-RFs was significantly different between FM patients and NC. Therefore WU-RF may be useful for assessing central sensitization of chronic pain patients in research and clinical practice.
PLoS ONE 02/2014; 9(2):e89086. DOI:10.1371/journal.pone.0089086 · 3.23 Impact Factor
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