Local application of capsaicin into the draining lymph nodes attenuates expression of adjuvant-induced arthritis.
Adjuvant-induced experimental arthritis (AA) was examined in adult male Lewis rats after isolated capsaicin (CAPS)-induced loss of small, nonmyelinated, afferent fibers in lymph nodes draining the site of adjuvant challenge. AA was induced by intradermal injection of Freund's complete adjuvant (CFA) into the subplantar area of the right hind paw. Controls received similar injections of mineral oil, the vehicle for CFA. One day later, half of the CFA-treated rats and half of the mineral oil-treated rats received injections of CAPS bilaterally into the draining lymph nodes (DLN). The DLN of remaining rats were injected with 50:50 ethanol/sterile physiological saline, the vehicle for CAPS. This paradigm resulted in four groups designated: CFA/CAPS, CFA/vehicle, vehicle/CAPS and vehicle/vehicle. Since substance P (SP) is present in small, nonmyelinated, afferent fibers, the target of the neurotoxin, CAPS, a radioimmunoassay specific for SP was used to verify the loss of these nerve fibers. CAPS injections into the DLN resulted in a loss in SP concentration in the DLN, with no depletion of SP in the spleen or sciatic nerve. These findings support the destruction of SP-containing nerves, which we interpret as verification of the selective loss of small, non-myelinated afferent nerves in the DLN with no significant spread of the neurotoxin to the nearby sciatic nerves which supply small, nonmyelinated, afferent fibers to the hind limb joints. Also, preservation of SP content in spleen indicates CAPS did not circulate via the lymphatic drainage. No chronic inflammation was observed in the fore or hind limbs from rats treated with the vehicle for CFA (vehicle/vehicle, vehicle/CAPS) at any time during the study. In CFA/vehicle-treated rats, bilateral, symmetrical inflammation of the hind limbs was apparent 14 days after challenge with CFA, and became progressively more inflamed through day 20. In contrast, hind limb inflammation in arthritic rats treated with CAPS was not symmetrical. On days 14 and 20 after challenge with CFA, the inflammatory response in the left hind limb, contralateral to the site of CFA injection, was significantly (p < 0.05) attenuated compared with the response seen on the right side of CFA/CAPS-treated rats, and with the response seen in left hind limb of CFA/vehicle-treated animals. In fact, the mean dorsoplantar width of contralateral hind limbs from CFA/CAPS-treated animals was not different from that measured in non-AA control groups. These findings support a role for small, nonmyelinated, sensory nerves that modulate immune responses in DLN in the development and progression of AA in Lewis rats.
Lorton
D
D
Hoover Arthritis Center, Sun Health Research Institute, Sun City, Arizona 85372, USA. dlorton@mail.sunhealth.org
Lubahn
C
C
Engan
C
C
Schaller
J
J
Felten
D L
DL
Bellinger
D L
DL
D000344:Afferent Pathways / Q000187:drug effects; D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D002211:Capsaicin / Q000008:administration & dosage / Q000627:therapeutic use*; D003714:Denervation; D005620:Freund's Adjuvant / Q000633:toxicity; D006614:Hindlimb; D007272:Injections, Intralymphatic; D008198:Lymph Nodes; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000502:physiology
D013373:Substance P; D005620:Freund's Adjuvant; D002211:Capsaicin