NMDA receptor antagonism limits visceral hypersensitivity and may offer an approach to functional gut disorders

DailyUpdates 26th March 2004: Functional bowel disorders account for the majority of gastroenterological referrals. British researchers have now discovered that targeting the NMDA receptor may limit visceral hypersensitivity, a major component of this group of disorders.

Approximately 9% of the US population suffers from moderate to severe non-cancer-related pain, a figure that includes 40-70 million individuals with chronic pain. This condition precipitates other serious pathologies such as depression and is associated with an estimated pharmaceuticals market of US$18.7 billion worldwide.

Visceral pain represents one particularly common subtype of pain and includes the common syndromes, irritable bowel syndrome (IBS) and functional upper GI disorders. IBS affects up to 10% of the US population and is associated with an annual expenditure of more than $8 billion, and accounts for 12% of primary care visits and 28% of the referrals to gastroenterologists. Functional upper GI complaints are also common in the primary care setting, accounting for 30 to 50% of referrals to gastroenterologists.

One speculated mechanism of visceral hypersensitivity is an activity-dependent increase in spinal cord neuronal excitability (central sensitization), which is dependent on activation of the N-methyl-D-aspartate (NMDA) receptor.

In their recent paper published in the March edition of Gastroenterology, Willert et al describe the role that the NMDA receptor plays in the development and maintenance of human visceral hypersensitivity.

In their Gastroenterology paper this group based at Hope Hospital in the United Kingdom studied healthy subjects using a randomized, double-blind, placebo-controlled, crossover design. Pain thresholds to electrical stimulation were determined both in the proximal esophagus and in the foot (control) before and after a 30-minute distal esophageal infusion of acid.

The NMDA receptor antagonist, ketamine, had no effect on either esophageal or foot pain thresholds in the absence of acid infusion however acid-induced esophageal hypersensitivity was prevented by ketamine without affecting foot pain thresholds. The effects of ketamine were observed when the drug was administered either before of after the administration of acid.

The authors conclude therefore that NMDA receptor antagonism may be of therapeutic benefit in the treatment of patients with esophageal sensitivity. Further studies investigating more recently developed antagonists and the effects of antagonists on other conditions associated with visceral hypersensitivity will hopefully improve the options available to clinicians serving this unmet market.

(source DailyUpdates 26th March; for a full abstract of the original paper see Gastroenterology. 2004 Mar;126(3):683-92)