Morphine and
tramadol are the
opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or additive anti‑nociceptive activity) induced potent anti‑nociceptive effect by co‑administration of
morphine and
tramadol. Identification of new strategies that can potentiate
analgesic effects of
opioids will be good therapeutic approaches for
pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tail‑flick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of
morphine induced an anti‑nociceptive effect in non‑sensitized and morphine‑sensitized mice. We found that infusion of
tramadol produced an anti‑nociceptive response in non‑sensitized mice, whereas
tramadol in doses of 0.5 and 1 μg/mouse induced
analgesia in morphine‑sensitized mice. Co‑injection of a non‑effective dose of
tramadol or
morphine (0.25 μg/mouse) with different doses of
morphine or
tramadol (0.25, 0.5, and 1 μg/mouse) respectively potentiated the
analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between
morphine and
tramadol in non‑sensitized and morphine‑sensitized mice. Our data indicated that both
morphine and
tramadol elicit more anti‑nociceptive response in
morphine sensitized mice; there is a synergistic effect between
morphine and
tramadol upon induction of
analgesic effect in non‑sensitized and morphine‑sensitized mice.