The spinal biology in humans and animals of pain states generated by persistent small afferent input

Abstract

Behavioral models indicate that persistent small afferent input, as generated by tissue injury, results in a hyperalgesia at the site of injury and a tactile allodynia in areas adjacent to the injury site. Local tissue injury and inflammation yields well-defined escape behaviors in animals and pain reports in humans. Examination of the histochemistry and electrophysiology of spinal systems has revealed considerable detail regarding the elements of systems that are activated by these stimuli. Nevertheless, the functional contribution of different spinal systems in pain processing ultimately must be defined in terms of the systems in which such end points can be measured, e.g., the behavior of the intact organism. We will consider below how certain spinal systems contribute to the observed behavioral states. Behavioral Effects of Cutaneous Stimuli After InjuryAn acute, unconditioned, thermal, or mechanical stimulus sufficient to activate polymodel nociceptive afferents (C fibers) depolarizes populations of dorsal horn wide dynamic range (WDR) neurons that project supraspinally. This output in turn evokes a supraspinally organized escape behavior. The hot plate test (thermal stimulus to the paw) or the local injection of an irritant such as formalin or capsaicin where the unconditioned stimulus evokes a somatotopically directed behavior (e.g., withdrawal or licking) are behavioral paradigms believed to reflect this underlying mechanism (1). The more intense the stimulus, the more robust will be the afferent volley and the more vigorous or shorter latencied is the escape behavior (2).An acute stimulus of intensity and duration that leads to tissue injury also produces an acute discharge. In addition, the injury leads to the local release of active factors that evoke and sustain persistent activity in the sensory afferents innervating the injured or inflamed tissue (3). Thus, in contrast to the acute response, injury leads to persistent activity in populations of small afferents and also may activate afferent populations that are excited only in the presence of local factors generated by the injury (e.g., silent ''nociceptors'') (4). Electrophysiological studies have shown that the persistent activation of spinal WDR neurons by small, but not large, afferents, will lead: (i) a progressive enhancement of the WDR response to each subsequent input, and (ii) an increase in the dimensions of the peripheral receptive field to which the spinal neuron will respond (5). This electrophysiological observation parallels behavioral changes in which the animal displays an enhanced response to a given stimulus or a reduction in the intensity of the stimulus required to evoke an escape response. Thus, the injection of an irritant (formalin) into one hind paw evokes a high frequency barrage during the first 10-20 min followed by a modest ongoing discharge over the next hour (6). Coincident with the initial afferent barrage, WDR neurons display an initial burst of activity followed by a period of quiescence and then a progress...

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