It is generally accepted that classical opioids exert their antinociceptive effect mainly when binding to opioid receptors located in the central nervous system. However, a growing body of evidence points to the relevance of peripheral opioid receptors in periphery pathology, including cancer. A cancer is very often the cause of pain resulting from peripheral metastasis. The peripheral component of antinociception induced by a dimeric enkephalin analog – biphalin showing limited blood-brainbarrier permeability may prove important in cancer pain therapy. An additional advantage of biphalin is a possibility to treat pain symptoms with reduction of side-effects – a result of the central action of some other opioid analgesics, e.g. morphine. We examined the peripheral and central analgesic effect of biphalin in a murine skin cancer pain model developed by an intraplantar inoculation of B16T0 melanoma cells. Animals developed robust thermal hypersensitivity in the tumor-bearing paw compared to PBS-injected individuals. Biphalin produced stronger analgesia in the tumor-bearing paw than morphine upon a comparable central effect. Our results suggest that biphalin analgesia manifested in the periphery is linked to a less effective transport through the bloodbrain barrier. We speculate that the centrally effective dose of biphalin equipotent to morphine simultaneously produces analgesia via peripheral opioid receptors. Thus, biphalin may become useful in cancer pain treatment as an alternative drug executing a local as well as a central analgesic response with limited undesirable side-effects.
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