Windup leads to characteristics of central sensitization

Saint Catherine University, Minneapolis, Minnesota, United States
Pain (Impact Factor: 5.21). 02/1999; 79(1):75-82. DOI: 10.1016/S0304-3959(98)00154-7
Source: PubMed


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.

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    • "It is caused by repeated stimulation of peripheral nerve Cfibers , leading to physiological changes, including progressively increased electrical response in the corresponding spinal cord (posterior horn) neurons. Experimentally, WU is often induced by repetitive low-frequency (0.3–5 Hz) electrical stimulation of peripheral C fibers; and could be measured as amplification of flexor reflex withdrawal and enlarged receptive field (Andersen et al., 2004; Andersen et al., 2005; Li et al., 1999; Spaich et al., 2005; Wall and Woolf, 1984). Similar changes are seen in central sensitization, defined (IASP Taxonomy) as increased responsiveness of nociceptive neurons in the central nervous system to their normal or sub-threshold afferent input (Mendell and Wall, 1965; Woolf and Thompson, 1991). "
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    ABSTRACT: Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.
    Full-text · Article · Oct 2015 · Experimental Neurology
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    • "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 [68], [69] 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 [46], [47]. "
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    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.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "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. "
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    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.
    Full-text · Article · Aug 2014 · European journal of pain (London, England)
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