Effect of cannabinoids on pain-stimulated and pain-depressed behavior in rats

Cannabinoids produce antinociception in many preclinical models of acute and chronic pain. In contrast, cannabinoids produce inconsistent analgesia in humans, showing little or no efficacy in treating acute pain, with modest efficacy in treating chronic inflammatory pain. This discrepancy may reflect an overreliance on preclinical assays of pain-stimulated behaviors, defined as behaviors that increase in rate or intensity following delivery of a noxious stimulus. In these assays, antinociception is indicated by a reduction in pain-stimulated behaviors, and antinociception is produced either by a reduction in sensory sensitivity to the noxious stimulus (i.e. true analgesia) or by false positive motor impairment. This dissertation addresses this weakness by complementing cannabinoid effects in conventional assays of pain-stimulated behavior with their effects in novel assays of pain-depressed behavior. Pain-depressed behaviors are defined as behaviors that decrease in rate or intensity following presentation of a noxious stimulus. Motor impairment does not produce false positive antinociception in assays of pain-depressed behavior, because antinociception is indicated by a blockade or reversal of pain-induced behavioral depression. In this dissertation, an intraperitoneal (IP) injection of lactic acid served as an acute noxious stimulus to stimulate stretching (pain-stimulated behavior) or depress intracranial self-stimulation (ICSS) (pain-depressed behavior), whereas, IP injection(s) of lipopolysaccharide (LPS) served as a chronic/acute inflammatory-related noxious stimulus to stimulate mechanical allodynia (pain-stimulated behavior) or depress ICSS (pain-depressed behavior). Cannabinoids tested in the assays of acid-stimulated stretching and acid-depressed ICSS included: mixed CB1R/CB2R agonists THC and CP55940, drugs that modulate levels of the endogenous cannabinoid agonist anandamide (URB597 and PF3845), and a selective CB2R agonist, GW405833. THC was also tested in assays of LPS-stimulated mechanical allodynia and LPS-depressed ICSS. In general, mixed CB1R/CB2R agonists were ineffective or exacerbated pain-depressed behavior regardless of noxious stimulus. Contrastingly, URB597 and GW405833 produced antinociception in the assay of acid-depressed ICSS; however their effects were not mediated by CBRs. All compounds produced antinociception in the assay of pain-stimulated behavior, except for PF3845. These results suggest that assays of pain-depressed behavior may be useful for development of cannabinoid analgesic medications, but that further research is needed to determine mechanisms underlying cannabinoid-mediated antinociception in these assays