Elsevier

Progress in Neurobiology

Volume 54, Issue 3, 8 January 1998, Pages 349-365
Progress in Neurobiology

SENSITIZATION OF PAIN PATHWAYS IN THE SPINAL CORD: CELLULAR MECHANISMS

https://doi.org/10.1016/S0301-0082(97)00067-1Get rights and content

Abstract

Sensitization is manifested as an increased response of neurones to a variety of inputs following intense or noxious stimuli. It is one of the simplest forms of learning and synaptic plasticity and it represents an important feature of nociception. In the spinal cord, repeated stimulation (at constant strength) of dorsal root afferents including nociceptive C fibres can elicit a progressive increase in the number of action potentials generated by motoneurones and interneurones. This phenomenon is termed “action potential windup” and is used as a cellular model of pain sensitization developing at the level of the central nervous system. Understanding the mechanisms responsible for windup generation might allow clarification of the cellular mechanisms of pain signalling and development of new strategies for pain treatment. Action potential windup is observed in a minority of cells only, indicating that certain cell-specific mechanisms are responsible for its generation. The most reliable index to predict windup generation is the rate at which the membrane potential is depolarized during repetitive stimulation. This phenomenon has been proposed to be due to gradual recruitment of NMDA receptor activity, to summation of slow excitatory potentials mediated by substance P (and related peptides) or to facilitation of slow calcium channels by metabotropic glutamate receptors. Little is known about the role of synaptic inhibition in windup, although it should not be underestimated. Each theory per se is unable to account for all the experimental observations. Since NMDA receptors are involved in many forms of synaptic plasticity, additional mechanisms such as summation of slow peptidergic potentials, facilitation of slow Ca2+ currents and disinhibition are proposed as necessary to impart specificity to pain-induced sensitization. These additional mechanisms might be species specific and change during development or chronic pain states.

Introduction

Nociception is a specialized form of sensory signalling which conveys information about impending (or actual) tissue damage. Pain is defined as “perception of an aversive or unpleasant sensation that originates from a specific region of the body” (Kandel et al., 1991). Not all nociceptive signals are perceived as pain and vice versa not every pain sensation originates from nociception. Nevertheless, pain perception is in most cases related to heightened sensitivity to sensory information from the region of the body which experiences nociceptive stimuli. This phenomenon is termed sensitization and it consists of increased neuronal responsiveness which is set up following repeated (or sustained) stimulation of noxious intensity. Once sensitization has developed it may last for long periods and is characterized by enhanced responses to even weaker stimuli. Sensitization is also considered as one of the simplest forms of learning (Kandel et al., 1991). Since sensitization persists after nociceptive stimuli have ceased (see, for example, Perl et al., 1976; Woolf, 1983), it is used as a model to study memory storage processes: in fact, the study of long-lasting sensitization in Aplysia helped in the discovery of several key elements of neuronal memory (Bartsch et al., 1995; Zhang et al., 1997).

As the mechanisms of sensitization throughout the central nervous system are complex and diverse, their comprehensive treatment is beyond the scope of the present review. Hence, we adopt a more focussed approach by addressing the question of sensitization of nociceptive pathways in the spinal cord which is the first central relay station for processing nociceptive information in vertebrates. Studies of relatively simple neuronal systems such as the one of Aplysia suggest that an elementary neuronal network may be sufficient to bring about sensitization and that the molecular substrates underlying this phenomenon can be identified (Bartsch et al., 1995; Cohen et al., 1997; Zhang et al., 1997). It seems likely that comparable network and cellular mechanisms in the spinal cord of vertebrates are responsible for analogous phenomena although with an added degree of complexity introduced by the sheer size of the circuit involved.

The present review will chiefly examine the mechanisms which determine the onset of sensitization in spinal cord and the associated short-term changes in synaptic efficacy rather than any long-term changes since the cellular mechanisms of the latter remain largely elusive (Woolf and Doubell, 1994; Thompson et al., 1995; Xu et al., 1995; Choi et al., 1996; Herrera and Robertson, 1996; Wilson and Kitchener, 1996). Nevertheless, even by narrowing the discussion field, it will be soon apparent that sensitization is a complex phenomenon far from being fully understood.

Section snippets

Sensitization of spinal nociceptive reflexes includes a central component

Since, by definition, sensitization is a simple increase in response to stimulation, this effect can theoretically occur at any point from nociceptors in peripheral tissues to brain areas which specifically respond to nociceptive inputs. In the case of mammals, this process spans from skin receptors via dorsal root ganglia, spinal cord, and brainstem to the thalamus and somatosensory cortex because, in each one of these structures, there are neurones responding specifically to noxious stimuli (

Cellular events underlying sensitization: definition and general characteristics

In theory, there are at least three general explanations for sensitization at cellular level: first, a widespread increase in cell responsiveness in the network unaccompanied by changes in synaptic connections; second, a decrease in the activity of cells which inhibit the responsive cells; and third, an extensive change in the network such as the emergence of new connections or loss of established ones. All three phenomena can occur in the spinal cord (Woolf et al., 1992; Thompson et al., 1993b

Action potential windup: an experimental model to investigate the development of sensitization at cellular level

To further the understanding of any biological process (including nociceptive sensitization), one needs an appropriate model, the basic features of which can be readily reproduced with a suitable experimental approach. The work of Woolf and his colleagues led to the use of the “windup” phenomenon as the most convenient model of sensitization investigated at single cell level (Woolf, 1983; Woolf and Wall, 1986; Thompson et al., 1990). Action potential windup (or simply windup) is an increase in

Receptor mechanisms involved in windup

In this section, data indicating involvement of particular classes of receptors in the generation of windup will be briefly reviewed.

Putative mechanisms of windup

This section will consider some putative mechanisms of windup: the term putative stems from our personal view that no mechanism has so far obtained unassailable experimental evidence at the single-cell level to make it the principal responsible process. Even with this interpretative constraint it seems possible to put forward three main hypotheses (Section 6.1Section 6.2Section 6.3), all based on a direct increase in cell responsiveness to incoming stimuli but differing in the identification of

Putative mechanisms responsible for long-term sensitization

Our present survey has mostly dealt with immediate changes in synaptic efficiency during sensitization. There is, additionally, a whole field of research concerned with long-term changes induced by pain. Space constraints will prevent its review as it is a very complex phenomenon: instead, we will note a few aspects of the relationship between short and long-term changes.

In addition to short-term (<1 hr) sensitization, there is a form of long-term sensitization which occurs in chronic pain and

Comparison of nociceptive input sensitization with long-term plastic changes in synaptic efficacy of other networks

Woolf and Walters (1991)suggested that the process of synaptic plasticity underlying nociceptive sensitization is based on fundamental synaptic mechanisms preserved through widely different species such as Aplysia, rat and man. According to this theory a number of major properties of central sensitization are also found to characterize a well-known type of synaptic plasticity, namely LTP, dependence on NMDA receptor activity, Ca2+ influx, and protein phosphorylation. In addition to these

Conclusions

The main conclusion of this short review is that in the spinal cord multiple cellular mechanisms can contribute to sensitization and windup of nociceptive inputs. Sensitization is just one aspect of the process of synaptic plasticity in the brain: as such it often includes NMDA receptor activation which upregulates excitatory synaptic transmission. The genesis of windup is no exception to this norm but it also seems to require, depending on species, developmental stage and/or cell type,

Acknowledgements

The authors' work was supported by grants from CNR, INFM and MURST to A.N; G.B. held a fellowship from ICGEB.

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