Perineural resiniferatoxin prevents the development of hyperalgesia produced by loose ligation of the sciatic nerve in rats.
BACKGROUND
The vanilloid receptors (TRPV1) are found in peripheral nerve fibers; their stimulation by capsaicin leads to release of calcitonin gene-related peptide and other neuropeptides participating in neuroinflammation. On the other hand, various inflammatory mediators, released after nerve damage, can activate or sensitize the TRPV1 receptors. These findings together suggest a protective effect of TRPV1 receptor blockade in neuropathy. In the present study, we tested the hypothesis that perineural resiniferatoxin (RTX) can prevent the development of hyperalgesia caused by placing loosely constrictive ligatures around the sciatic nerve.


METHODS
Male Sprague-Dawley rats received a single percutaneous injection of RTX (0.0005%, 0.1 mL) or vehicle at the sciatic nerve, and underwent surgery 3 h later to place four loose ligatures around the nerve on the side of drug administration. Responses to noxious heat (withdrawal latency, paw-lift duration), repetitive stimulation with von Frey filaments, and changes in hindpaw posture (toe spread, ventroflexion, and foot exorotation) were assessed.


RESULTS
Perineural RTX administered before surgery completely prevented ligation-induced reduction in withdrawal latency, increase in paw lift duration and increase in withdrawal frequency to von Frey filaments. The preventive effect of RTX on the development of deficits in hindpaw posture was pronounced but not complete, e.g., on day 7 after surgery, the cumulative paw-posture score (0-6) was 1.69 +/- 0.92 with RTX and 4.06 +/- 1.68 with vehicle (P < 0.005). The effect of RTX used against the background of already developed neuropathy was limited to thermal hypoalgesia lasting for a relatively short period.


CONCLUSIONS
Perineural RTX prevents the development of neuropathy caused by placing loosely constrictive ligatures on the sciatic nerve. Perioperative use of drugs acting via the TRPV1 receptors may hold the promise for preventing neuropathic pain after surgery on peripheral nerves.
Kissin
Igor
I
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. kissin@zeus.bwh.harvard.edu
Freitas
Cristina F
CF
Bradley
Edwin L
EL
D000818:Animals; D004224:Diterpenes / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010525:Peripheral Nerves / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000502:physiology
D004224:Diterpenes; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C024353:resiniferatoxin