Opiates are powerful analgesics, but their clinical use is hindered by side effects, tolerance, and concerns about dependence and addiction. A resolution to this problem may be provided by the paradoxical effects of ultra-low-dose opioid antagonists. Recently we found that this phenomenon extends to the cannabinoid system.
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In standard doses, opioid antagonists such as naloxone or naltrexone block the effects of morphine and other opiates. Khem Jhamandas, in the Department of Pharmacology and Toxicology, has demonstrated that ultra-low doses of opiate antagonists enhance the analgesic properties of morphine, and reduce the development of analgesic tolerance to these drugs. We demonstrated that these effects were not confined to analgesia: ultra low dose naltrexone also extended the duration of morphine's rewarding effect in the conditioned place preference paradigm. While this initial work on reward used sub-analgesic doses of morphine, subsequent work, conducted in collaboration with Pain Therapeutics Inc. demonstrated that ultra-low-dose naltrexone blocks the acute rewarding effects of analgesic doses of both morphine and oxycodone, as well as the motivationally aversive effects of withdrawal from their chronic administration. In addition, the analgesic effects of ultra-low dose antagonists are not a motor artifact in that the same doses do not alter the cataleptic effects of morphine. Although the mechanisms underlying the paradoxical effects of ultra-low-dose anatatonists are not fully understood, molecular pharmacology work showed that ultra-low-dose opioid antagonist co-treatment attenuates a switch in G protein coupling that occurs following chronic administration of the opiate alone. Taken together, these studies have important implications for long-term pain management. Indeed, these paradoxical effects could help those with chronic pain who require prolonged opiate therapy.
Tuerke, K.J., Paquette, J.J., Beninger, R.J. & Olmstead, M.C. (2011).
Dissociable effects of ultra-low dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine. Behavioural Pharmacology, 22, 558-563.
Burns, L.H., Leri, F. & Olmstead, M.C. (2006). Ultra-low-dose naltrexone reduces dependence and addictive properties of opioids. In: Dean, R., Bilsky, E., Negus, S. & Wickens J. (Eds.). Opioid Receptors and Antagonists: From Bench to Clinic. Volume in Contemporary Neuroscience Series.
Olmstead, M.C. & Burns, L.H. (2005). Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats. Psychopharmacology, 181, 576-581.
Wang, H.-Y., Friedman, E., Olmstead, M.C. & Burns, L.H. (2005). Ultra-low-dose naloxone attenuates chronic morphine-induced changes in Mu opioid receptor – G protein coupling and G βγ signalling. Neuroscience, 135, 247-261.
Powell, K.J., Abul-Husn, N.S., Jhamandas, A., Olmstead, M.C., Beninger, R.J. & Jhamandas, K. (2002). Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance and reward. Journal of Pharmacology and Experimental Therapeutics, 300, 588-596.
Cannabinoid Mechanisms in Pain and Analgesia
Building on our work with ultra-low dose opioid antagonists, Jay Paquette examined ways to improve the analgesic effects of cannabinoid drugs, which are approved for pain treatment in Canada. These drugs act at the CB1 receptor and exert effects similar to opioid drugs. This drug interaction may be explained by the fact that µ opioid and CB1 receptors are co-localized on spinal and supra-spinal neurons and have similar neural signal-transduction mechanisms. The work of our colleagues Khem Jhamandas and Catherine Cahill, among others, has shown that opioids have biphasic effects: ultra-low doses (i.e., pM to nM range) of opioid agonists stimulate, rather than inhibit, cellular activity, and this effect can be blocked by ultra-low doses of an opioid antagonist. Ultra-low doses of opioid antagonists also enhance the analgesic effect of opioid agonists, extend the duration of opioid-induced analgesia, prevent the development of tolerance, and reverse established tolerance. Because of the interaction between cannabinoid and opioid systems, Jay Paquette investigated whether the interaction is also expressed at the ultra-low dose level. Using rats and the tail-flick test of antinociception, we showed that ultra-low doses of an opioid antagonist dose dependently enhance cannabinoid-induced antinociception. In a second set of experiments, ultra-low doses of a CB1 receptor antagonist paradoxically enhanced the duration of cannabinoid-induced antinociception. In collaboration with colleagues in New York, we uncovered a molecular mechanism of these ultra-low dose cannabinoid effects, which involves a shift from an inhibitory to a stimulatory G-protein coupled mechanism. These findings suggest that the paradoxical effects of opiate antagonists (see previous project description) may extend to other pharmacological systems.
Paquette, J.J. Wang, H-Y., Bakshi, K. & Olmstead, M.C. (2007).
Cannabinoid-induced tolerance is associated with a CB-1 receptor G-protein coupling switch that is prevented by ultra-low dose rimonabant. Behavioural Pharmacology, 18, 767-776.
Paquette, J.J. & Olmstead, M.C. (2005). Ultra-Low Dose Naltrexone Enhances Cannabinoid-Induced Antinociception. Behavioural Pharmacology, 16, 597-603.