In a recent post on DrugMonkey, the DM suggested that I write a post on clinical trials for cannabinoids as analgesics. Due to some obligations I am quite sure that I am unable to talk about certain aspects of these trials; however, I can talk about about their rationale and why the public should know that cannabinoid analgesics need not have any association with cannabis smoking.
Let’s start this off with a little background on why cannabinoids are analgesic. Human’s have known that cannabis smoking can be analgesic for thousands of years but it is only recently that we learned why. Soon after the first cannabinoid receptor, CB1, was cloned, Andrea Hohmann and Miles Herkenham at NIH began a series of elegant studies examining the expression of cannabinoid receptors in the central nervous system (CNS) and how this expression pattern was relevant to pain. They found that CB1 receptors were expressed in the outer lamina of the spinal cord, suggesting that CB1 receptors might be involved in pain control (since this is where pain-sensing neurons first terminate in the CNS). Subsequently, it was shown that spinal injection of cannabinoids induced analgesia and that knockdown of CB1 receptor by antisense led to increased pain (hyperalgesia). These studies were done largely by Ken Hargreaves’ group. All of these findings suggested that an endogenous spinal cannabinoid system was involved in pain control. These were really the first studies to suggest a mechanism of action (MOA) for cannabinoid analgesia in the CNS.
Around the same time, two groups, Ian Meng in Howard Field’s lab and another led by the late (and far too soon I might add) J Michael Walker, demonstrated that cannabinoids could induce analgesia via another mechanism, this one also in the CNS. CB1 receptors are expressed in a particular area of the periaqueductal grey (PAG). The PAG is a major pain control center and is often considered to be the location of the brain where endogenous opioids mediate analgesia (think runner’s high). Walker’s work showed that PAG cannabinoid receptor containing neurons exerted control over neurons in the rostroventralmedial medulla (RVM). This is important because the RVM sends projections down to the spinal cord and these neurons are responsible for controlling synaptic output at the level of the outer lamina of the spinal cord. Essentially what happens is that cannabinoids activate CB1 receptors in the PAG. These neurons then modulate the output of the RVM such that the RVM exerts descending inhibition on the outer lamina of the spinal cord. All of this leads to analgesia. Hence, in the CNS, there are two major loci of cannabinoid action to cause analgesia, the outer lamina of the dorsal horn of the spinal cord and the PAG. Continue reading