Antinociceptive Effects of Interleukin-4, -10, and -13 on the Writhing Response in Mice and Zymosan-Induced Knee Joint Incapacitation in Rats

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Abstract
The antinociceptive effects of interleukin (IL)-4, -10, and -13 were investigated in two different experimental pain models. Our results showed that pretreatment (30 min) with IL-4 (1–5 ng/animal), IL-10 (0.4–10 ng/animal), or IL-13 (0.4–2.5 ng/animal) inhibited the writhing response induced by the i.p. administration of acetic acid (53–89%) or zymosan (63–74%) in mice, and the knee joint incapacitation induced by i.a. injection of zymosan (49–66%) in rats. Neither of the cytokines affected the pain elicited in mice using the hot-plate test. This analgesic effect of IL-4, -10, and -13 was not reversed by the combined pretreatment with the opioid receptor antagonist naloxone. IL-4, -10, or -13 significantly inhibited the release of both tumor necrosis factor (TNF)-α (60, 53, and 100%, respectively) and IL-1β (80, 100, and 100%, respectively) by mice peritoneal macrophages obtained after local (i.p.) injection of zymosan. Antisera against IL-4, -10, and -13 potentiated both the zymosan-induced writhing response and the articular incapacitation. Our results demonstrate that IL-4, -10, and -13 display analgesic activity that is probably not due to endogenous opioid release. This analgesic effect could be related to a peripheral mechanism, probably via the inhibition of the release of the pro-inflammatory cytokines TNF-α and IL-1β by resident peritoneal macrophages.