Abstract
Ultra-low doses of alpha-2 (α2)-adrenoceptor antagonists augment spinal morphine antinociception and inhibit tolerance, but the role of receptor specificity in these actions is unknown. We used the stereo-isomers of the α2 adrenoceptor antagonist, efaroxan to evaluate the effect of receptor specificity on the induction of spinal morphine tolerance and hyperalgesia. Tail flick and paw pressure tests were first used to evaluate high dose efaroxan (12.6μg) and its stereo-isomers on clonidine analgesia in intrathecally catheterized rats. Ultra-low doses of individual isomers (1.3ng) were then co-administered with morphine (15μg) to determine their effects on acute antinociceptive tolerance and hyperalgesia induced by low dose spinal morphine (0.05ng). Results demonstrate that high dose (+) efaroxan antagonized clonidine-induced antinociception, while (−) efaroxan had minimal effect. In addition, an ultra-low dose of (+) efaroxan (1.3ng), substantially lower than required for receptor blockade, inhibited the development of acute morphine tolerance, while (−) efaroxan was less effective. Racemic (±) efaroxan effects were similar to those of (+) efaroxan. Furthermore, low dose morphine (0.05ng) produced sustained hyperalgesia in the tail flick test and this was blocked by co-injection of (+) but not (−) efaroxan (1.3ng). Given the isomer-specific efaroxan effects and their different receptor potencies, we suggest that inhibition of opioid tolerance by ultra-low dose efaroxan involves a specific interaction with spinal α2-adrenoceptors in this model. Likewise, inhibitory effects of adrenoceptor antagonists on morphine tolerance may be due to blockade of opioid-induced hyperalgesia.
Highlights
Repeated systemic or spinal opioid administration produces analgesic tolerance (Christie, 2008), a phenomenon linked to the induction of progressive and latent hyperalgesia with a consequent loss of drug potency (Chu et al, 2006)
When the (À ) isomer of efaroxan was co-injected with clonidine, the resulting antinociceptive effects in the tail flick test were not significantly different compared to clonidine alone (Fig. 1C)
The present study used a model of acute morphine tolerance and efaroxan stereo-isomers to investigate whether the actions of an a2-adrenoceptor antagonist in modulating opioid analgesia and tolerance are due to interaction at the a2-adrenoceptor
Summary
Repeated systemic or spinal opioid administration produces analgesic tolerance (Christie, 2008), a phenomenon linked to the induction of progressive and latent hyperalgesia with a consequent loss of drug potency (Chu et al, 2006). Ultra-low doses of competitive opioid receptor antagonists such as naltrexone have been shown to paradoxically augment spinal morphine analgesia and inhibit or reverse the development of this opioid tolerance (Powell et al, 2002; Chindalore et al, 2005; Mattioli et al, 2010). We have shown that ultra-low dose a2 adrenoceptor antagonists both prevent and reverse established analgesic tolerance to morphine (Milne et al, 2008), a finding subsequently confirmed by Lilius et al (2012). We have shown that ultra-low doses of structurally diverse a2-adrenoceptor antagonists (atipamezole, yohimbine, mirtazipine, and idazoxan) increase the acute antinociceptive effects of morphine, block the induction of acute as well as chronic tolerance, and effectively reverse established tolerance to spinal morphine in tests of
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