Wind-up of spinal cord neurones and pain sensation: much ado about something?

Abstract

Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning. Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors. However, most drugs capable of reducing the excitability of spinal cord neurones, including opioids and NSAIDs, can also reduce or even abolish wind-up. Thus, other theories involving synaptic efficacy, potassium channels, calcium channels, etc. have also been proposed for the generation of this phenomenon. Whatever the mechanisms involved in its generation, wind-up has been interpreted as a system for the amplification in the spinal cord of the nociceptive message that arrives from peripheral nociceptors connected to C-fibres. This probably reflects the physiological system activated in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses. On the other hand, wind-up, central sensitisation and hyperalgesia are not the same phenomena, although they may share common properties. Wind-up can be an important tool to study the processing of nociceptive information in the spinal cord, and the central effects of drugs that modulate the nociceptive system. This paper reviews the physiological and pharmacological data on wind-up of spinal cord neurones, and the perceptual correlates of wind-up in human subjects, in the context of its possible relation to the triggering of hyperalgesic states, and also the multiple factors which contribute to the generation of wind-up.

Introduction

Wind-up is a progressive, frequency-dependent facilitation of the responses of a neurone observed on the application of repetitive (usually electrical) stimuli of constant intensity (see Fig. 1, Fig. 2, Fig. 3). The phenomenon of wind-up was first described by Lorne Mendell (Mendell and Wall, 1965, Mendell, 1996) as a frequency-dependent facilitation of spinal cord neuronal responses mediated by afferent C-fibres. Mendell suggested that this phenomenon may be due to a reverberatory activity evoked by afferent C-fibres in interneurones of the spinal cord lasting for 2–3 s. “If in this period of time another stimulus arrives to the cord, it sums with the ongoing activity to produce a more intense discharge in the interneurones than the one before it” (Mendell, 1996). More than thirty years after the first description of this phenomenon, the mechanisms underlying the generation of wind-up are not fully established, and there is little consensus as to the role of wind-up in spinal cord physiology/pathophysiology, despite the hundreds of papers that have been published on this subject.

In the past ten years or so, wind-up has been studied more intensively for two reasons. First, the discovery by two different groups (Davies and Lodge, 1987; Dickenson and Sullivan, 1987) that the blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors inhibited the generation of wind-up. Second, the observation that there were prolonged increases in the excitability of dorsal horn neurones subsequent to the application of a wind-up evoking stimulus (Cervero et al., 1984; Cook et al., 1987). This led to the proposal (Cook et al., 1987, Dickenson, 1990) that there was a causal relationship between wind-up and the hyperexcitability of spinal cord nociceptive neurones observed after peripheral damage known as ‘central sensitisation’ (Woolf, 1983b).

These two factors were further linked by the observation that NMDA receptor antagonists inhibited both wind-up and central sensitisation in a nociceptive reflex preparation (Woolf and Thompson, 1991). These authors suggested that NMDA receptor-sensitive wind-up was a necessary prelude to the induction of central sensitisation. Thereafter, various authors have proposed that wind-up initiates and maintains central sensitisation, and that it could be used as an experimental model to study what happens in spinal cord neurones in situations of central sensitisation leading to hyperalgesia (Baranauskas and Nistri, 1998, McMahon et al., 1993, Price, 1996, Urban et al., 1994b).

However, we now know that the excitatory amino acids are not the only family of neuromediators in the spinal cord involved in the generation of wind-up. Tachykinin receptor antagonists, opioids or even non-steroidal anti inflammatory drugs (NSAIDs) with a central action also depress wind-up. On the other hand, the direct relationship between wind-up and hyperalgesia has been questioned in the past few years (Magerl et al., 1998, Woolf, 1996). It has become clear that hyperalgesia and central sensitisation can occur in the absence of wind-up (De Felipe et al., 1998, Laird et al., 1995, Woolf, 1996), and that wind-up and central sensitisation are separate phenomena, although they may share common mechanisms (Magerl et al., 1998, Li et al., 1999). It is therefore still unclear how wind-up is generated and whether or not wind-up has a physiological meaning.

In the present review, we have tried to address these questions by examining the main lines of thought in the interpretation of wind-up, the characteristics of wind-up in the different experimental preparations used, the involvement of different families of neuromediators in the generation and maintenance of wind-up, the new phenomenon of Aβ-fibre evoked wind-up, etc. in an attempt to present in a systematic way the current data on wind-up and to give our view as to what wind-up might represent in physiological terms.