Central Sensitization Theory of Migraine: Clinical Implications

The clinical science of migraine headache continues to evolve. Theories of the pathophysiology of migraine have progressed from the early vascular basis of migraine to more complex current theories that emphasize the centrality of neuronal dysfunction. The most recently articulated theory of migraine is the central sensitization hypothesis, which proposes that altered processing of sensory input in the brainstem, principally the trigeminal nucleus caudalis, could account for many of the temporal and symptomatic features of migraine, as well as its poor response to triptan therapy when such treatment is initiated hours after the onset of pain. Both preclinical and clinical data support the central sensitization theory. A critical clinical implication of this theory is that drugs that are capable of either aborting or arresting the process of central sensitization, most prominently dihydroergotamine, may have a unique role in the treatment of migraine. An additional, and highly practical, implication is based upon the finding that cutaneous allodynia—pain arising from innocuous stimulation of the skin, as in hair brushing or the application of cosmetics—is an easily identifiable marker of central sensitization. Thus, the presence or absence of cutaneous allodynia can be integrated into the routine clinical assessment of migraine and utilized as a determinant of treatment. Future basic and clinical research on central sensitization is likely to be of ongoing importance to the field.     

Role of pylorus in mediating cholecystokinin-stimulated satiety in the Zucker rat

Obese Zucker rats are less responsive than their lean littermates to the effects of cholecystokinin-octapeptide on satiety and pancreatic growth and exocrine function. We hypothesized that the hyperphagia observed in obese Zucker rats may be caused by a decreased pyloric contractile response to cholecystokinin, resulting in an increased rate of gastric emptying, decreased postprandial gastric distention, and thus decreased satiety. Pyloric muscle strips from six obese Zucker rats and six lean littermates were mounted in separate tissue baths and isometric contraction was measured in response to acetylcholine and cholecystokinin-octapeptide. The dose-response curves for acetylcholine-and cholecystokinin-octapeptide-stimulated pyloric muscle contraction were similar for both the obese and the lean rats. (For cholecystokinin, D₅₀ obese=4.0±0.6 nM, D₅₀ lean=3.4±0.2 nM;P=0.16). We conclude that the decreased satiety response to cholecystokinin-octapeptide observed in obese Zucker rats is not secondary to a decreased pyloric responsiveness to cholecystokinin.This work was supported by NIH grant AM28303-03.     

Current status of colorectal cancer chemoprevention

Chemoprevention refers to suppression or reversal of the carcinogenic process using pharmacologic or nutritional agents. Colorectal carcinogenesis is a protracted, multistep process that offers opportunities for prevention. Aspirin and selective cyclooxygenase-2 inhibitors (coxibs) have been evaluated for the prevention of sporadic adenoma recurrence. Aspirin was shown to reduce adenoma recurrence rates in patients with prior colorectal neoplasms; however, the optimal dosage remains unclear. Recent studies of coxibs indicate that these agents are effective in reducing sporadic adenoma recurrence, but chronic use can result in serious cardiovascular toxicity. These data underscore the need for chemopreventive agents with acceptable risk-to-benefit ratios. In this regard, nitric-oxide-releasing aspirin shows chemopreventive efficacy in preclinical models and holds promise for reduced toxicity in humans. Furthermore, ongoing chemoprevention trials are evaluating nutritional supplements, such as folic acid and selenium, and results are eagerly awaited.