Exploring the basis of cannabinoid analgesia in humans

Cannabis is historically used to provide analgesia (pain relief) but how it does so remains debatable. Of the cannabinoids (cannabis-like drugs) derived from cannabis, delta-9-tetrahydrocannabinol (?-9-THC) is found to provide analgesia in patients. Animal studies have shown that ?-9-THC and other cannabinoids work by activating ‘receptors‘ which are found in pain processing areas of the brain. However, such results cannot always be translated to man, and further development of cannabinoids for use in patients requires better understanding of how and where they act in the human brain. This can be achieved by using functional magnetic resonance imaging to record how the various brain areas respond to pain when influenced by ?-9-THC. The imaging technique is well-established and the studies would be undertaken in healthy volunteers in whom experimental pain can be safely and reversibly induced. The research would provide insight into the functions of specific brain areas during pain processing and inform the development of future cannabinoids that target them for pain relief.

Pain is a major therapeutic target for cannabis-based medicines. Of the naturally occurring cannabinoids, delta-9-tetrahydrocannabinol (?-9-THC) is known to be clinically efficacious. In humans, cannabinoid-1 (CB-1) receptor agonism accounts for the pharmacological effects of ?-9-THC. Although a mixed CB receptor agonist, animal studies have revealed that the analgesic effects of ?-9-THC are largely blocked by CB-1 antagonists. Considered together, these observations suggest that CB-1 based mechanisms underlie cannabinoid analgesia in humans. However information regarding the site of CB-1 agonism in this process remains unclear. CB-1 receptors are distributed within a pain-modulatory system that exerts control over the transmission of nociceptive input. While CB-1 receptors densely populate many regions (including limbic areas, basal ganglia and cerebellum), the amygdala may represent a pivotal site for cannabinoid analgesia afforded by CB-1 agonists. These cortical and sub-cortical structures modulate pain processing via facilitatory and inhibitory circuits descending from brainstem areas such as the periaqueductal grey and the rostral ventral medulla. These areas comprise the descending circuitry through which cannabinoid CB-1 receptor mediated analgesia may be expressed.

Functional magnetic resonance imaging (fMRI) studies would be used to translate the above concepts of cannabinoid analgesia derived from animal studies to human neurobiology. The supra-spinal components of the descending pain facilitating circuit substantiating capsaicin-induced central sensitisation in healthy volunteers would first be mapped. The modulatory effects of ?-9-THC on the imaging and psychophysical correlates of the experimental sensitisation state would then be examined to ascertain if anti-hyperalgesia forms the basis for the efficacy of the drug in neuropathic pain patients. The effects of ?-9-THC on the anticipation of pain would also be assessed as the central correlates of pain anticipation are CB-1 receptor dense and drug activity in these areas (cingulate cortex and cerebellum) may therefore be particularly relevant to clinical efficacy of cannabinoids.

A double-blinded placebo controlled cross-over design would be employed in these studies. In addition to pain psychophysics, validated questionnaires would be used to assess if mood or personality is associated with the development of central sensitisation or analgesia afforded by CB receptor agonism. Data obtained from the overall research would extend considerably our understanding of human cannabinoid pharmacology and inform the development of drugs that target the endo-cannabinoid system for pain relief.