Evidence for Alterations in Descending Pain Modulation

Since the beginning of the 20th century it has been known that the brain can tonically inhibit spinal cord excitability, thereby regulating the amount of peripheral sensory information reaching the central nervous system. More recent evidence has demonstrated the activity of both pain-inhibitory and -facilitatory mechanisms that can tonically and phasically regulate spinal cord excitability (55,62,63). While top-down tonic pain-inhibitory modulation appears to predominate in healthy individuals, an upregulation of descending pain-facilitatory systems has been demonstrated in the maintenance of hyperalgesia in animal models of peripheral nerve injury (64). An alteration in the balance between inhibitory and facilitatory pain-modulatory systems has been proposed as a possible mechanism underlying chronic pain syndromes such as fibromyalgia (65) and IBS (66,67). Zambreanu et al. were the first to demonstrate the activation of brain stem regions in the context of central sensitization in healthy human volunteers (68). Using 3T fMRI, they compared whole brain responses, including the brain stem, to punctuate mechanical stimulation in an area of secondary hyperalgesia (induced by heat/capsaicin sensitization model) or in a control area. They found greater activation during stimulation of the hyperalgesic region in several cortical regions, including posterior insula and anterior and posterior cingulate cortex, as well as the thalamus and pons. The brain stem activation was localized to the NCF and the PAG, two regions that receive inputs from corticolimbic networks (including the rostral ACC), send projections to the rostro-ventral medulla, and are part of a corticolimbic pontine pain modulation circuit (69,70). These intriguing findings correlate nicely with recent findings in rodents demonstrating the upregu-lation of spino bulbo spinal loops, which play a role in the maintenance of hyperalgesia following peripheral injury (64). There is preliminary evidence to suggest that patients with IBS may also show abnormal activation of brain stem regions involved in pain modulation, in particular a reduced activation of endogenous pain inhibition systems. Mayer et al. demonstrated that while healthy control subjects and asymptomatic patients with longstanding, quiescent ulcerative colitis showed normal activation of corticolimbic pontine pain modulation circuits, IBS patients showed significantly less activation of the pontine region (59). The limited spatial resolution of PET imaging used in this study did not allow identification of the specific brain stem nucleus involved. Wilder-Smith et al. performed an fMRI study in 10 female patients with IBS (5 constipated- and 5 diarrhea-predominant bowel habit) and 10 female healthy control subjects to test the hypothesis that IBS patients show abnormal activation of diffuse noxious inhibitory controls (DNICs) systems in response to a noxious stimulus (71). DNIC activation can be quantified by the perceptual modulation of a painful stimulus (in this case noxious rectal balloon distension) by a secondary heterotypically applied nociceptive stimulus (in this case ice water immersion of the foot). They found that subjective pain ratings of rectal volume distension by the heterotypic cold pain stimulus was reduced in healthy controls but not in the IBS patient group, suggesting an inadequate activation of DNICs in the patients. Interestingly, prior to the heterotypic pain stimulus, patients showed less activation in the ACC, pACC, and PFC during painful distension compared with baseline. This decreased activation is interpreted as possibly relating to a preexisting saturation of the entire pain/anxiety system or ceiling effect. Following the hete-rotypic cold stimulus, a complex set of differences in response to rectal pain were found among the controls and the two IBS subgroups (constipation and diarrhea). These included a decreased insular, thalamus, and PAG activation in the controls (perhaps reflecting the DNIC process) that was absent in the IBS subjects.

While intriguing, several methodological issues make this study more difficult to interpret and suggest further replication. First, the rectal stimuli were balloon volumes done manually using a syringe. Computer-controlled phasic pressure pulses using a barostat are known to give more accurate stimuli for sensory measurement. Pain thresholds determined in terms of distension volume do not allow differentiation of perceptual differences from differences in rectal compliance. Second, the small sample size and the subgrouping of IBS patients into even smaller samples further increase the potential unreliability of the pairwise group differences.

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