Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the alpha(2A)-adrenoceptor selective antagonist BRL44408

摘要

Ultra-low doses of non-selective alpha(2)-adrenoceptor antagonists augment acute spinal morphine antinociception and block morphine tolerance; however, the receptor involved in mediating these effects is currently unknown. Here, we used tail flick and paw pressure tests on the rat to investigate the acute analgesic and tolerance-inducing effects of spinal morphine and norepinephrine alone or in combination with an ultra-low dose of the alpha(2A)-adrenoceptor antagonist, BRL44408. We also assessed the potential antinociceptive effects of BRL44408 alone following spinal administration. A spinal close of BRL44408, over 1000-fold lower than that required to inhibit clonicline-induced antinociception (1.65 ng/10 mu L), significantly prolonged morphine and norepinephrine action in both nociception tests. Following repeated morphine or norepinephrine injections, 1.65 ng BRL44408 attenuated both the decline of antinociceptive effect and increase in morphine ED50 values, responses indicative of acute morphine tolerance. BRL44408 administered alone produced a delayed antinociceptive effect unrelated to repeated nociceptive testing. This response was partially reduced by the alpha(2)-adrenoceptor antagonist atipamezole (10 mu g). Ultra low dose BRL44408 was able to inhibit the loss of morphine- and norepinephrine-induced antinociceptive response, and prevent the loss of drug potency due to repeated agonist exposure. This implicates the spinal alpha(2A)-adrenoceptor subtype in the action of ultra low dose alpha(2)-adrenoceptor antagonists on morphine and norepinephrine tolerance. The BRL44408-induced analgesia is partially dependent on its interaction with the alpha(2)-adrenoceptors. Thus, this agent class may be useful in pain therapy. (C) 2014 Elsevier B.V. All rights reserved,