Published: 14.08.09
Pain research

Endocannabinoids can promote pain

The endocannabinoids occurring naturally in the human body are closely related to the active ingredients of the cannabis plant. Cannabis has been used for thousands of years, for example to treat chronic pain. However, the fact that the endocannabinoids produced by the body itself can also be involved in the origin of pain is the astonishing result of studies by a Zurich research team.

Simone Ulmer
Neuronal circuits in the spinal cord. When activated, pain fibres known as C-nociceptors release the excitatory chemical messenger glutamate in the spinal cord. This not only excites spinal neurons directly but also stimulates the production of endocannabinoids, which in turn reduce neuronal inhibition. Touch-evoked signals can now spread to pain cells. (Image: Hanns Ulrich Zeilhofer/ETH Zurich)
Neuronal circuits in the spinal cord. When activated, pain fibres known as C-nociceptors release the excitatory chemical messenger glutamate in the spinal cord. This not only excites spinal neurons directly but also stimulates the production of endocannabinoids, which in turn reduce neuronal inhibition. Touch-evoked signals can now spread to pain cells. (Image: Hanns Ulrich Zeilhofer/ETH Zurich) (large view)

The first mention of cannabis as a medicinal plant was in the Chinese book of medicinal plants “Shennong bencao jing”, which is almost 5000 years old. The Chinese emperor Shennong is said to have recommended cannabis resin as a remedy for various illnesses. After the use of its active ingredients for thousands of years to alleviate chronic pain, a study by the research group led by Hanns Ulrich Zeilhofer, Professor at the Institute of Pharmaceutical Sciences at ETH Zurich and the Institute of Pharmacology and Toxicology at the University of Zurich now shows that the endocannabinoids produced by the body itself can lead to pain sensitisation in certain types of pain. Their study was published last week in the scientific journal “Science”.

Short-circuit in the spinal cord

Pain and touch are conducted to the brain through the spinal cord via two different systems. This enables the brain to distinguish between pain and simple touch. However, because the two systems are interconnected via nerve fibres in the spinal cord, simple touches can also be perceived as pain, for example as a result of a “short circuit”. Such faulty circuits can occur if inhibitory chemical messengers (neurotransmitters) in the spinal cord are absent or blocked. Zeilhofer says, “This happens in various illnesses and can even be triggered by intense pain stimuli themselves.”

The body’s own endocannabinoids play a considerable part in the biochemical processes taking place in this, as the study by Zeilhofer and his team shows. In particular, the release of endocannabinoids in the spinal cord seems to be responsible for the fact that, after an initial pain stimulus, pain sensitivity spreads beyond the area originally stimulated. Even slight touch in this area is then perceived as painful. The endocannabinoids thus cause a “short circuit” between the touch signals and pain.

The scientists tested the theory that endocannabinoids released in the spinal cord during intense pain stimuli are responsible for this short-circuit. It actually became apparent that activating the endocannabinoid receptors on isolated spinal cord reduced the release of pain-inhibiting neurotransmitters. Animals that had developed the expected oversensitivity to slight touching after a pain stimulus behaved normally again after their cannabinoid receptors in the spinal cord were blocked.

Endocannabinoid inhibitors relieve pain

The fact that these processes also occur in humans was shown by experiments on healthy volunteers carried out in the Anaesthesiology Department at the University of Erlangen. Pain receptors in the volunteers’ skin were locally stimulated with an electric current, after which the size of the area hypersensitive to pain was determined. In the next step, half of the volunteers received a placebo for ten days, while the others were given Rimonabant, a substance that blocks certain cannabinoid receptors. The experiment was then repeated. Zeilhofer says, “The painful area formed in the test subjects whose endocannabinoid receptors had been blocked was about fifty percent smaller than in those who had taken the placebo.”

Helpful to the pharmaceutical industry

However, further experiments also showed that other forms of pain, e.g. those occurring as a result of nerve injuries, developed normally in mice that lacked endocannabinoid receptors. The endocannabinoids seem to play no major pain promoting role in this case. Zeilhofer says, “In the next step we want to find out which pain patients might possibly benefit from blocking the cannabinoid receptors. At any rate our findings should be of great interest to drug companies who are working with this pain model to develop new analgesics.”

 
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