resiniferatoxin and Pain--Postoperative

Vanilloid agonists (capsaicin, resiniferatoxin, [RTX]) applied to the peripheral nerves provide conduction blockade. In contrast to the analgesic component of conduction anesthesia produced by local anesthetics, vanilloid agonists provide conduction analgesia not associated with suppression of motor or sensory functions not related to pain. Vanilloid agonists provide conduction analgesia selectively because their effect on the nerve trunks is limited to C- and ADelta-fibers. RTX is much more potent than capsaicin and has a wider therapeutic window. In rat experiments, perineural RTX produced a long-lasting thermal and mechanical hypoalgesia with a very wide separation between effective concentrations (from 0.00003% to 0.001%) providing an effect lasting from several hours to several weeks. A nerve block with RTX prevented the development of thermal and mechanical hyperalgesia as well as pain behavior in a model of incisional pain. RTX-induced conduction blockade has an inherent drawback of TRPV1 agonists, the initial excitation (pain); therefore, a local anesthetic should be injected to prevent it. When RTX was applied to the rat's sciatic nerve in doses necessary to provide conduction analgesia, the frequency of unmyelinated fiber degeneration was more than an order of magnitude lower than that with the therapeutic concentration of lidocaine. These promising results should be confirmed by experiments in species other than rodents (pigs, sheep). Taken together, the data indicate possible clinical applicability of vanilloid-induced conduction analgesia.

Topics: Analgesia; Analgesics; Animals; Capsaicin; Diterpenes; Dose-Response Relationship, Drug; Humans; Hyperalgesia; Nerve Fibers; Neural Conduction; Pain, Postoperative; Rats; TRPV Cation Channels

Peripheral nociceptors expressing the ion channel transient receptor potential cation channel, subfamily V, member 1, play an important role in mediating postoperative pain. Signaling from these nociceptors in the peri- and postoperative period can lead to plastic changes in the spinal cord and, when controlled, can yield analgesia. The transcriptomic changes in the dorsal spinal cord after surgery, and potential coupling to transient receptor potential cation channel, subfamily V, member 1-positive nociceptor signaling, remain poorly studied.. Resiniferatoxin was injected subcutaneously into rat hind paw several minutes before surgical incision to inactivate transient receptor potential cation channel, subfamily V, member 1-positive nerve terminals. The effects of resiniferatoxin on postincisional measures of pain were assessed through postoperative day 10 (n = 51). Transcriptomic changes in the dorsal spinal cord, with and without peripheral transient receptor potential cation channel, subfamily V, member 1-positive nerve terminal inactivation, were assessed by RNA sequencing (n = 22).. Peripherally administered resiniferatoxin increased thermal withdrawal latency by at least twofold through postoperative day 4, increased mechanical withdrawal threshold by at least sevenfold through postoperative day 2, and decreased guarding score by 90% relative to vehicle control (P < 0.05). Surgical incision induced 70 genes in the dorsal horn, and these changes were specific to the ipsilateral dorsal horn. Gene induction with surgical incision persisted despite robust analgesia from resiniferatoxin pretreatment. Many of the genes induced were related to microglial activation, such as Cd11b and Iba1.. A single subcutaneous injection of resiniferatoxin before incision attenuated both evoked and nonevoked measures of postoperative pain. Surgical incision induced transcriptomic changes in the dorsal horn that persisted despite analgesia with resiniferatoxin, suggesting that postsurgical pain signals can be blocked without preventing transcription changes in the dorsal horn.

Topics: Analgesia; Animals; Disease Models, Animal; Diterpenes; Male; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Dorsal Horn

Chronic pain after thoracotomy has been reproduced in a rat model that allows investigation of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that morphine, clonidine, neostigmine, gabapentin, and bupivacaine reduce the incidence of allodynia in the rat postthoracotomy pain model. One purpose of this study was to test whether intercostal injection of resiniferatoxin (RTX) decreased the amount of allodynia in an animal model of chronic postthoracotomy pain. We also tested whether RTX induced a transient mechanical hyperalgesic response in uninjured animals.. Male Sprague-Dawley rats were anesthetized, and the right fourth and fifth ribs were surgically exposed. The pleura was opened, and the ribs were retracted. Intercostal RTX 0.8 or 8 microg was injected in animals that developed allodynia after surgery; a control group underwent rib retraction and received vehicle only. An additional group of uninjured animals received RTX. Rats were tested for mechanical allodynia at a predetermined area around the incision site for 3 wk.. Allodynia developed in 42% of the animals that underwent thoracotomy. A transient hyperalgesic response was noted in the uninjured group that underwent drug injections. Intercostal RTX did not modify the course of allodynia in injured rats.. The current results suggest that intercostal RTX causes a transient hyperalgesic response in uninjured animals and is ineffective in reducing the mechanical allodynia after thoracotomy.

Topics: Animals; Diterpenes; Hyperalgesia; Injections; Intercostal Nerves; Male; Nerve Block; Pain Measurement; Pain Threshold; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Thoracotomy

Topics: Capsaicin; Capsicum; Diterpenes; Humans; Pain, Postoperative; TRPV Cation Channels

Resiniferatoxin (RTX) is a vanilloid agonist with a unique spectrum of activities. Vanilloids bind to the transient receptor potential ion channel subtype 1, a nonselective cation ionophore important in the integration of different noxious signals. Vanilloid agonists selectively decrease sensitivity to noxious stimuli. In this study, we sought to determine whether perineural RTX prevents hyperalgesia in a model of incisional pain. In a rat model, RTX was administered percutaneously to the sciatic and saphenous nerves before the plantar incision. The withdrawal response to von Frey filaments, the struggle response to pressure on the paw, and pain scoring based on weight bearing were measured before RTX and at various intervals for 8 days after RTX. A percutaneous injection of RTX (0.0003%) to the sciatic (0.1 mL) and saphenous (0.05 mL) nerves completely prevented incisional hyperalgesia. Two hours after incision, the withdrawal threshold was 51 mN without and 456 mN with RTX (P < 0.0001). RTX also prevented the incision-induced decrease in struggle threshold and abolished the pain behavior associated with weight bearing. We conclude that RTX provides a type of neural blockade when postoperative pain is abolished and that nonpainful sensations and motor functions are preserved.

Topics: Anesthetics, Local; Animals; Diterpenes; Dose-Response Relationship, Drug; Hyperalgesia; Male; Pain, Postoperative; Rats; Rats, Sprague-Dawley

Topics: Animals; Diterpenes; Hyperalgesia; Pain, Postoperative; Rats