T-type Ca2+ channel involvement in visceral pain

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 syndrome, irritable bowel syndrome (IBS). 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.

In this edition of TherapeuticAdvances we highlight research supporting the development of T-type Ca2+ channel modulators as treatments of visceral pain. As research into ion channels continues to identify novel targets for multiple and diverse diseases, therapeutic successes surrounding the development of channel modulators will boom (for a full overview of this area, Click here to access Ion Channel Assays in the Drug Discovery Process). Numerous companies are engaged in R&D programs involving ion channels in a number of areas, and drugs targeting ion channels already generate over $6 billion in sales per annum.

A variety of different ion channels are involved in controlling neural membrane potential. Low voltage-activated (LVA) T-type Ca2+ channels have recently been shown facilitate pain signals in peripheral nociceptors and in the spinal cord. T-type channels are also highly expressed in the thalamus, through which noxious signals from the spinal cord must pass before reaching the cortex. When the thalamocortical relay neurons receive sensory inputs, they respond with dual firing modes: either with singular action potentials or with a burst of action potentials clustered together as a high-frequency discharge. T-type Ca2+ channels are known to excite hyperpolarized thalamic neurons to generate bursts of action potentials.

Genetically modified mice with a functional deletion of T-type currents have recently been shown by Kim et al to lack low threshold burst firing in the thalamocortical relay neurons. These mice responded normally to mechanical or thermal stimulation of the skin and to Freund’s adjuvant, however they exhibited an exaggerated response to intraperitoneal irritants. These findings suggest that T-type channels can inhibit visceral nociception. The proposed analgesic activity does not appear to be mediated by peripheral T-type channels since pharmacological inhibition of these receptors caused dose-dependent analgesia. In contrast infusion of a T-type channel inhibitor into the ventroposterolateral thalamus enhanced pain responses. Electophysiological studies demonstrated that intraperitoneal acetic acid increased single spikes in ventroposterolateral neurons, a pattern followed by burst spikes, which reflected the activation of T-type channels, and a reduction in single spikes. T-type channel deleted mice failed to respond to acetic acid with burst spikes and subsequent reduction in single spikes.

These results suggest that T-type Ca2+ channels in ventroposterolateral neurons are first activated after a surge of pain signal influx from the viscera and then play an inhibitory role in the processing of those signals, thereby suppressing pain responses. The development of pharmacological strategies able to activate these ventroposterolateral T-type Ca2+ channels may therefore offer one approach to the treatment of visceral hypersensitivity disorders.

Entry date Wednesday, November 12, 2003

Adapted from Kim et al, Science. 2003 Oct 3;302(5642):117-9.