Ultra-Low Dose Antagonist Effects on Cannabinoids and Opioids in Models of Pain: Is Less More?
Paquette, Jay J.
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An ultra-low dose of a drug is approximately 1000-fold lower than the dose range traditionally used to induce a therapeutic effect. The purpose of the present thesis was to broaden the knowledge of the ultra-low dose effect, that was previously identified in the opioid receptor system, by looking at whether opioids and cannabinoids interact at the ultra-low dose level, whether cannabinoid receptors themselves demonstrate the ultra-low dose antagonist effect, and whether the opioid ultra-low dose effect is maintained in a model of persistent, unavoidable pain. For experiment 1, separate groups of Long Evans rats were tested for antinociception following an injection of vehicle, the cannabinoid agonist WIN 55 212-2 (WIN), the opioid antagonist naltrexone (an ultra-low or a high dose), or a combination of WIN and naltrexone doses. Ultra-low dose naltrexone elevated WIN-induced tail flick thresholds without extending its duration of action. In experiment 2, antinociception was tested in rats following either acute or sub-chronic (7 days) injections of vehicle, WIN, ultra-low doses of the CB1 receptor antagonist rimonabant (SR 141716), or a combination of WIN and ultra-low dose rimonabant. Following the chronic experiment, striatal tissue was rapidly extracted and subjected to co-immunoprecipitation to analyse CB1 receptor coupling to G-protein subtypes. Ultra-low dose rimonabant extended the duration of WIN-induced antinociception, and attenuated the development of WIN-induced tolerance. Animals chronically treated with WIN alone had CB1 receptors predominately coupling to Gs proteins, whereas all other groups had CB1 receptors predominately coupling to Gi proteins. For experiment 3, all animals were subjected to the formalin test following either acute or sub-chronic injections of vehicle, the opiate morphine, ultra-low doses naltrexone, or a combination of morphine and ultra-low dose naltrexone. Ultra-low dose naltrexone had no significant effect on morphine-induced pain ratings in either the acute, or sub-chronic drug treatments. This thesis provides evidence that the ultra-low dose effect, including the agonist-induced G-protein coupling switch, extends to another receptor type. This effect may, therefore, be part of a generalized principle that applies to many G-protein coupled receptors.