Endogenous modulatory networks can either facilitate or inhibit pain[42,43]. Endogenous analgesia refers to systems that produce the latter. These systems involve a network that includes higher cortical (e.g., anterior cingulate cortex) and subcortical regions (e.g., the amygdala, hypothalamus) that project to brainstem nuclei (periaqueductal gray and raphe nuclei) that send projections to the dorsal horn [44] These systems can be modulated by a number of factors including stress, pain and the placebo response [42].
A number of studies have used fMRI to investigate endogenous modulation of pain (Table 4) and map circuits involved in CNS systems that can alter decrease or increase pain [45-47]. Most of these studies involved attention or distraction to modulate circuits. In addition, closely linked with this are studies of placebo response, evaluation of the effects of attention and expectancy, of empathetic reactions to pain in others, to producing "trickery" of the brain by sensory inputs [48].
Perhaps of greatest importance are studies of the placebo effect since there has been a significant literature in this domain from psychophysical studies [49,50]. A neurobiology and neurocircuitry were predicted for the placebo effect based on its effects on analgesia. [51]. Indeed the general circuitry of the placebo response can be applied to non-painful stimuli. These and other studies have enhanced our knowledge of the interaction of physiological pain circuits and cognitive/emotional circuits [52]. The use of imaging has now clearly established how some of these endogenous systems operate. This understanding coupled with an objective method of evaluating placebo should provide novel insights into drug development as well as the treatment of patients with acute and chronic pain.
Complementary with fMRI studies on placebo, the use of fMRI has identified neural systems involved in anxiety and fear related to pain. These two reactions to pain are important both from a neuroscience aspect. [16] as well as from practical applications of treating patients. While fear and anxiety have been considered to have different effects on neural processing [53], recent fMRI studies have begun to explore this issue [54].
The innate nature of the pain experience is clearly indicated by studies showing that activations in non-sensory CNS systems in an observer experiencing empathetic pain, are similar to those produced in a subject by noxious stimuli. The study of endogenous analgesia highlights the opponent systems operating in pain. In addition, fMRI studies reveal that in addition to the sensory pathways activated in endogenous analgesia and pain processing, reward/aversion circuitry is activated, with reward related to pain relief and aversion related to pain. [21]. The balance between these opponent systems may be crucial in determining the overall sensory and emotional experience of pain in chronic pain states.
fMRI has also been applied to exploring the neurobiology of acupuncture, which is believed to activate endogenous analgesic mechanisms [55]. Such studies have predominantly been in healthy subjects using experimental pain. The evidence for the benefit of acupuncture for clinical studies has been mixed. For example, recent studies in migraine patients has indicated that acupuncture may be no more effective than sham acupuncture in reducing migraine headaches, although both are more effective than no intervention. Such studies need to be repeated, but raise questions as to how acupuncture works (for example, through activation of diffuse noxious inhibitory controls or activation of endogenous systems through expectancy etc.) [56]. In carefully devised studies, defining brain circuits involved in expectancy, treatment etc. may help provide a more objective evaluation of such interventions.
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