We examined the effect of the subcutaneous (s.c.) pretreatment of formalin into both hind paws of mice on the antinociception induced by the intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administration of ${eta}$-endorphin using the tail-flick test. Pretreatment with formalin ($5\%$) for 5 h had no affect on the i.c.v. administered ${eta}$-endorphin-induced tail-flick response. However, pretreatment with formalin for 40 h attenuated the tail-flick inhibition induced by i.c.v. administered ${eta}$-endorphin. This antinociceptive tolerance to i.c.v. ${eta}$-endorphin continued up to 1 week, but to a lesser extent. Pretreatment with formalin for 5 and 40 h significantly reduced the i.t. ${eta}$-endorphin-induced inhibition of the tail-flick response, which continued up to 1 week. The s.c. formalin treatment increased the hypothalamic pro-opiomelanocortin (POMC) mRNA level at 2 h, but this returned to the basal level after 40 h. Our results suggest that the increase in the POMC mRNA level in the hypothalamus appears to be involved in the supraspinal or spinal ${eta}$-endorphin-induced antinociceptive tolerance in formalin-induced inflammatory pain.