Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation

Abstract

Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys. Either RTX (three animals) or vehicle (one animal) was directly infused (20 microl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed. Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean +/- standard deviation]): blinks, 25.7 +/- 4.4 compared with 106.6 +/- 20.8; eye wipes, 1.4 +/- 0.8 compared with 19.3 +/- 2.5; and squinting, 1.4 +/- 0.6 seconds compared with 11.4 +/- 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons. Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.