B vitamins potentiate acute morphine antinociception and attenuate the development of tolerance to chronic morphine in mice

Abstract

Objectives. Opiate analgesics are the most effective treatments for severe pain, but their clinical utility is often hampered by the development of analgesic tolerance. There are striking similarities between morphine actions and neuropathic pain. We have demonstrated that B vitamins can attenuate neuropathic pain after peripheral nerve injury, sensory neuron inflammation/compression, and transient spinal cord ischemia. Given this similarity, the present study investigated whether B vitamins might be able to modify the antinociceptive effect of morphine as well as morphine tolerance in mice. Methods. Cell signaling was assayed byWestern blot and immunohistochemistry. Antinociception was assessed in ICR mice using the tail flick. The effects of B vitamins on acute morphine-induced antinociception and chronic morphine tolerance were studied. Results. 1) Co-administration of B vitamins with morphine potentiates acute morphine antinociception. 2) B vitamins attenuate the development of antinociceptive tolerance to chronic morphine administration and inhibit morphine-induced p-NR1, p-PKC in the spinal cord. 3) Morphine induces microglial activation, as evidenced by increased p38 MAPK phosphorylation, IBA1, and IL-1β in the spinal cord, and these changes are inhibited by B vitamins. 4) Treatment of B vitamins alone shows no notable effects on pain threshold and activity of microglia in vivo. Conclusions. B vitamins potentiate acute morphine antinociception and attenuate chronic morphine tolerance.