Homeostasis is defined as the process of maintaining a constant internal environment, and an important concept is that nociceptors provide vital inputs to homeostatic processes by signalling imbalance in the internal and external environments. It is becoming clear that a number of different CNS structures participate in mediating affective responses to nociceptor stimulation. Indeed, it is likely that this central co-ordination provides the framework for differences in the patterns of autonomic change and emotional response that are evoked by different types of nociceptive inputs. For instance, nociceptive inputs from different body regions evoke different patterns of cardiovascular response. More specifically, cutaneous pain evokes increases in arterial pressure and tachycardia whilst responses to deep somatic or visceral pain may include decreases in arterial pressure and bradycardia (Bandler & Shipley, 1994). This presentation will focus on the roles played by the periaqueductal grey (PAG) and the hypothalamus, including their interactions, in mediating cardiovascular responses to nociceptive inputs that arise from different peripheral domains and that are conveyed in different classes of nociceptive primary afferents.
The anatomical organisation and the physiological consequences of activity in the descending control systems that originate in the hypothalamus and PAG have received a great deal of attention. However, the stimuli that activate these systems are less well understood, despite the fact that they undoubtedly become active as part of the pain experience. At the present time, the peripheral nociceptive inputs to the PAG are the best understood. It is now recognised that the PAG is organised in the form of a number of longitudinal columns that run parallel to the aqueduct. As a result of studies that have used the induction of Fos protein as a marker of neuronal activation, it has been proposed that neurones in the lateral and ventrolateral subdivisions of the PAG are activated in response to different environmental cues: the lateral columns being more concerned with processing afferent information related to cutaneous insults, and the ventrolateral sector being more concerned with deep somatic and visceral pain.
Nociceptive inputs are conveyed to the spinal cord in unmyelinated C-fibres and finely myelinated Aδ-fibres. The C-fibre component of the nociceptive message mediates the slowly conducted, poorly localised aspects of the pain signal that are exaggerated in chronic pain states. In contrast, the Aδ input is believed to mediate the sensori-discriminative aspects of acute pain. Visceral nerves contain a relatively high proportion of C-fibres and, as a consequence, visceral pain may be expected to be conveyed principally by activity in C fibres, in contrast to cutaneous pain which may result from both C and Aδ activation. Thus differential activation of the lateral and ventrolateral columns could be more directly related to the type of nerve fibre activated rather than the location of the particular end organ. This view is supported by the results of our studies that described significantly more Fos-positive neurones in the ventrolateral PAG in response to preferential activation of cutaneous C-nociceptors than in any other subdivision.
Our recent studies are revealing similar findings with regard to the role of the hypothalamus in co-ordinating cardiovascular responses to noxious stimuli. A focus of noxious visceral input into regions of the anterior hypothalamus from which sympathoinhibitory responses can be evoked has been identified in electrophysiological studies and, in a companion study that combined retrograde tracing with visualisation of Fos protein, nociceptive inputs from viscera were found to activate hypothalamic neurones that projected to the ventrolatral PAG, i.e. those parts which co-ordinate passive coping strategies including depressor responses and bradycardia. In contrast, in a related study, we were unable to find any neurones activated by noxious cutaneous stimulation that projected to the ventrolateral sector of the PAG. Furthermore, ongoing studies (Parry et al. 2001) have revealed that neurones in localised regions of the anterior hypothalamus are driven by peripheral C-nociceptor input and that a considerable proportion (24 %) of these cells project to the ventrolateral PAG, whereas less project to its dorsolateral sector.
These studies indicate that the different columns of the PAG may be recruited to mediate the co-ordinated patterns of response evoked from the hypothalamus. In particular, they provide evidence that visceral and C-nociceptor inputs drive hypothalamic-midbrain pathways that are confined almost exclusively to the ventrolateral sector of the PAG. Such circuitry may provide the framework for mediating passive coping strategies in response to visceral, diffuse or chronic pain.This work was supported by The Wellcome Trust.
- Bandler, R. & Shipley, M.T. (1994). Trends in Neuroscience 17, 379-389.
Parry, D.M., Semenenko, F.M., Simpson, D.A.A., McMullan, S. & Lumb, B.M. (2001). J. Physiol. 536.P, 46P.