In addition to conduction analgesia, vanilloid agonists can be used to provide other types of peripheral analgesia such as topical, intraarticular, intravesicular, and infiltration analgesia. These approaches are associated with the effects of vanilloids on the peripheral terminals of the primary afferent neurons. Targets of the vanilloid actions in the peripheral terminals are different from those in the nerve fibers. For example, mechanisms of peptide release from the nerve endings represent the targets different from those in the nerve trunks. There are a number of indications that peripheral nerve terminals are more sensitive to capsaicin than the nerve trunks (57
). Topical capsaicin has been used clinically as an adjuvant analgesic in a variety of pain conditions including postherpetic neuralgia, painful diabetic neuropathy, and postmastectomy pain syndrome (2
). Capsaicin and RTX intravesicular (urinary bladder) administrations have been found effective in the treatment of detrusor hyperreflexia (75
). An intraoperative (total knee arthroplasty) instillation of capsaicin solution (5 mg in 50 mL) into the wound (with bupivacaine) has been recently tried to provide a long-term postoperative analgesia with the positive outcome (15
The application of vanilloid agonists to peripheral nerve terminals resulted in the loss of nerve fiber visualization determined with immunohistochemical methods (58
). However, in a study of the effects of topical capsaicin (1%) applied to the eye of rats electron microscopy could not detect signs of nerve degeneration in the cornea (63
). As indicated above, the parallel use of immunohistochemical and electron microscopic methods for the investigation of the changes of the terminal axons in the rat urinary bladder following intravesical capsaicin or RTX also indicated the absence of axon degeneration despite disappearance of immunohistochemical staining (62
). These results question the equation of TRPV1 staining disappearance with neuronal loss when axonal traffic is blocked. The clinical effects of topical capsaicin or RTX could be explained by degeneration of terminal axons if these vanilloids are used in high concentrations. Nerve terminals probably have much higher sensitivity to vanilloid agonists than the nerve fibers. Therefore, degeneration of the nerve terminals following local application of vanilloid agonists is more likely than degeneration of nerve fibers following their application to the nerve trunks. However, the possibility of long-lasting defunctionalization without degeneration cannot be excluded even for topical application of vanilloid agonists. Their concentration probably determines the difference between inactivation without degeneration and inactivation with irreversible damage to the nerve terminals when the nerve functions can recover only due to regeneration.
The Iadarola group suggested the use of selective ablation of the nociceptive primary afferents as a way to delete neurons involved in pathological pain process (72
). They suggested three strategies for pain modulation based on different applications of RTX: topical, intraganglionic, and intrathecal. Intrathecal RTX was used in a canine bone cancer model with positive results (79
). The authors suggested that the therapeutic effect of RTX is due to its action on the neuronal cell bodies in the dorsal root ganglia. However, the dorsal horn terminals of primary afferents can also be the target of intrathecal RTX. Central terminals of primary afferents can be as highly sensitive to vanilloid agonists as peripheral terminals. The conclusion on the in vivo neuron degeneration was based on immunohistochemistry. Nevertheless, selective neurolytic block with high concentrations of RTX is an exciting possibility.