Importance of anti- and pro-nociceptive mechanisms in human disease.

T he burden of chronic pain to society is enormous. This is both in terms of physical and emotional impact to individuals and carers, in addition to the large financial burden. Current estimates suggest that 11.5–55.2% of individuals worldwide are defined as suffering from chronic widespread pain. A major characteristic of functional disorders such as irritable bowel syndrome (IBS) and inflammatory/ neuropathic disorders such as gastrooesophageal reflux and chronic pancreatitis is abdominal discomfort or pain. There is an increasing awareness that many similarities exist mechanistically between somatic chronic pain conditions and the pain witnessed as chronic in IBS and chronic pancreatitis patients. With this realisation there has been a change of focus for researchers of both somatic and visceral pain conditions from peripheral structures as the preferred target of research to the central nervous system (CNS). It has long been recognised that the CNS has a major modulating nociceptive influence that alters resultant pain perception. Recent developments in neuroimaging have enabled CNS investigations of visceral pain processing in patients and controls and such studies have highlighted the additional relevance of cognitive and emotional factors in modulating pain perception from physical changes such as plasticity and sensitisation. Imaging studies have provided valuable objective information on what is inherently a subjective phenomenon, that for too long has relied upon patients giving a self report of their pain using coarse pain rating scales. Currently, there is a wider imaging literature on pain processing from somatic structures compared with visceral organs. This is probably because it is experimentally (and ethically) easier to perform somatic acute pain paradigms in healthy controls (for instance, using noxious thermal events) compared with more challenging oesophageal or rectal balloon distensions. However, this situation is rapidly changing and in terms of investigating relevant patient groups with pain conditions, there is a rapidly growing literature investigating visceral pain syndromes that competes with imaging studies investigating neuropathic or inflammatory pain (the interested reader is referred to these excellent reviews on imaging pain in the literature). Since 1906 we have known that the brain can modulate in a ‘‘top-down’’ manner spinal cord excitability via a tonically active influence that is largely inhibitory in function. Evidence to support this came from work by Sherrington who showed that nociceptive reflexes were enhanced after the spinal cord was transected. Reynolds in 1969 again emphasised the relevance of this phenomenon by showing that focal electrical stimulation in the rat midbrain periaqueductal gray (PAG) produced analgesia strong enough to permit surgery. Over the years, further work showed that stimulation of several brain sites, including the sensory cortex, thalamus, hypothalamus, midbrain, pons, and medulla, produced inhibitory effects on spinal nociceptive processing, suggesting an integrated network of brain regions that produce anti-nociceptive influences in situations where it is desirable to not be behaviourally diverted due to the noxious input. Such situations could include those where there is high arousal as in sports or battle or during placebo analgesia. Many electrophysiological, anatomical, and pharmacological studies determined that these descending influences on spinal nociceptive processing relied on relays in the rostroventral medulla (RVM), including the medial nucleus raphe magnus and it is now accepted that the RVM is the final common output for descending influences from rostral brain sites (for an excellent review see Gebhart 2004 and Porreca et al, 2002). The focus of research on these descending influences was on inhibitory anti-nociceptive effects, with surgical applications for the treatment of chronic pain using periventricular electrical stimulation. In the 1990s, pioneering work by Gebhart and colleagues established without doubt the additional presence of descending facilitatory influences on spinal nociceptive processing. Independent work led by Fields et al had focused on characterising the response properties of cells within the RVM and showed that two major types of neurones were present: ‘‘ON’’ and ‘‘OFF’’. This work by Fields et al paved the way for understanding better the role of the RVM in relation to processing and ‘‘top-down’’ modulation of pain. ‘‘OFF’’ cells are thought to comprise a descending inhibitory system that attenuates nociceptive information directly at the level of the spinal cord (anti-nociception) 18 whereas ‘‘ON’’ cells have a facilitatory influence on nociceptive processing through descending systems projecting to the spinal cord (pro-nociceptive). 18 The functional role of anti-nociception in everyday life and its importance is relatively easy to grasp; stress, fear, intense exercise, or escaping from a predator when injured are a few situations where control of pain has an obvious value to the behaving animal. However, to understand the functional role of pro-nociception in everyday life is less easy. Again, pioneering work by Gebhart and other colleagues unequivocally established a role for the RVM in the maintenance of hyperalgesic states following peripheral nerve injury. When tissue is injured there is increased input and sensitivity to stimulation at the site of injury; this is called primary hyperalgesia and is caused by increased excitability of peripheral nociceptors. More importantly, there is also increased sensitivity to stimuli from uninjured tissue either surrounding or distal to the site of injury; this is called secondary hyperalgesia and is caused by changes in excitability of neurones in the CNS or ‘‘central sensitisation’’. Most work has focused on spinal cord changes during generation of central sensitisation but the work described above on pro-nociceptive influences provided an alternative explanation for the generation and maintenance of secondary hyperalgesia. Work from the laboratories of Gebhart, Porreca, and others have clearly established the importance of such ‘‘spinobulbo-spinal’’ loops in hyperalgesia and possibly the development of chronic pain. 15 19 Indeed, recent work from our laboratory using FMRI in a human COMMENTARIES 1553