SENSITIZATION OF PAIN PATHWAYS IN THE SPINAL CORD: CELLULAR MECHANISMS
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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