Analgesic roles of peripheral intrinsic met-enkephalin and dynorphin A in long-lasting inflammatory pain induced by complete Freund's adjuvant in rats

Previous studies have focused on strategies for pain relief based on the peripheral opioid system. However, little is known with regard to the profile of the peripheral opioid system in long-lasting inflammatory pain. In the current study, the intrinsic changes of the peripheral opioids were investigated in long-lasting inflammatory pain. A rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain was established. Paw swelling and thermal hyperalgesia (paw withdrawal latency, PWL) were analyzed until day 18 after the CFA injection. The levels of peripheral opioids and their upstream inducers, corticotrophin-releasing factor (CRF) and interleukin (IL)-1 beta, were measured, and validation experiments were performed using opioid receptor antagonists. Long-lasting inflammatory pain was successfully induced in the rats, as shown by the significantly increased paw swelling and decreased PWLs. On day 18 after the CFA injection, the IL-1 beta levels were significantly elevated, while CRF remained at a normal level in the paw inflammatory tissue. In addition, met-enkephalin (Met-ENK) and dynorphin A (DYN A) levels were significantly increased, while the beta-endorphin level remained normal. Local intraplantar administration of delta- and kappa-opioid receptor antagonists resulted in more substantial pain, but did not significantly affect the PWLs of the normal control rats. Therefore, the results indicated that the increased levels of local Met-ENK and DYN A in CFA-induced long-lasting inflammatory pain may be involved in peripheral intrinsic analgesia.