Vanilloid receptor ligands: hopes and realities for the future

Neurons possessing C-fibers transmit nociceptive information into the central nervous system and participate in various reflex responses. These neurons carry receptors that bind capsaicin, recently identified as the vanilloid VR1 receptor. Excitation of these cells by capsaicin is followed by a lasting refractory state, termed desensitisation, in which the neurons fail to respond to a variety of noxious stimuli. Desensitisation to capsaicin has a clear therapeutic potential in relieving neuropathic pain and ameliorating urinary bladder overactivity, just to cite 2 important examples. Vanilloids may also be beneficial in the treatment of benign prostate hyperplasia (BPH). Since the majority of elderly patients have neuropathic pain co-existent with urinary incontinence and/or BPH, a drug that ameliorates pain and improves urinary symptoms at the same time promises to be of great clinical value in geriatric medicine. In fact, capsaicin has already been shown to have a role in the treatment of conditions that can arise in the elderly, including herpes zoster-related neuropathic pain, diabetic neuropathy, postmastectomy pain, uraemic itching associated with renal failure, and urinary incontinence. The potent VR1 agonist resiniferatoxin, now in phase II clinical trials, appears to be superior to capsaicin in terms of its tolerability profile. Recent discoveries enhance the therapeutic potential of vanilloids. The recognition that VR1 also functions as a principal receptor for protons and eicosanoids implies that VR1 antagonists may be of value in the treatment of inflammatory hyperalgesia and pain. Animal experimentation has already lent support to this assumption. The discovery of VR1-expressing cells in the brain as well as in non-neural tissues such as the kidney and urothelium places VR1 in a much broader perspective than peripheral pain perception, and is hoped to identify further, yet unsuspected, indications for vanilloid therapy. The realisation that VR1 and cannabinoid CB1 receptors have overlapping ligand recognition properties may also have far-reaching implications for vanilloid therapy. In fact, arvanil, a combined agonist of VR1 and CB1 receptors, has already proved to be a powerful analgesic drug in the mouse. From academic molecular biology laboratories to industrial drug discovery centres to the clinics, there is a steady flow of new data, forcing us to constantly revise the ways we are thinking about vanilloid receptor ligands and their hopes and realities for the future. This review covers the most promising current trends in vanilloid research with special emphasis on geriatric medicine.