Neurotransmitters Involved with Cannabinoid Action

Cannabis is a complex mixture of cannabinoid molecules (over 61 have been identified) and other chemicals (of which 400 have been identified); with THC as the main active cannabinoid responsible for the psychotropic effects. All these chemicals may have a wide variety of mechanisms of action and that of their metabolites may well be different again. So far, studies have concentrated on THC and a number of synthetic analogues, revealing a number of possible mechanisms of action.

The central nervous system (CNS) transmitters that modulate the perceptions of pain include noradrenaline, serotonin (5HT), acetylcholine, GABA, the opioid peptides and the prostaglandins. Reports suggest that the analgesic effects seen with the cannabinoids involve prostaglandins, noradrenaline, 5HT and the opioid peptides, but not GABA or acetylcholine. The involvement of the prostaglandins is complex. The cannabinoids are stimulators of phospholipase A2, promoting the production of prostaglandins, but also inhibitors of cycloxygenase therefore also inhibiting production. The scene is further complicated by the fact that prostaglandins oppose pain centrally but cause pain at peripheral sites (). This may explain why in some tests involving cutaneous electrical pain stimulation to the finger tips in human subjects, cannabis increased sensitivity to both painful and nonpainful stimulation and reduced tolerance to pain ().

The mechanism of the anti-inflammatory effect of THC has been investigated by Burstein et al. (). They explain that THC inhibited prostaglandin synthesis in an in-vitro system by reducing the conversion of arachidonic acid to prostaglandin E2. It was also found to be an inhibitor of the formation of prostaglandin E1. Cannabidiol was found to be far more active than THC in this test suggesting a structural relationship between analgesic and anti-inflammatory activity among the cannabinoids. It is also proposed that the cannabinoids interfere with prostaglandin action on adenylate cyclase which is reported to mediate pain perception. Levonantradol, a cannabinoid derivative from Pfizer Laboratories also inhibits prostaglandin induced diarrhoea in animals ().

The involvement of 5HT as a mediator for analgesia with the cannabinoids is debatable. Analgesia is potentiated in the mouse tail flick test by 5-hydroxytryptophan (the precursor of 5HT) and imipramine (a 5HT re-uptake inhibitor) and the cannabinoids are known to affect 5HT. However intrathecally injected methysergide (a 5HT antagonist) has no effect on THC induced analgesia.

The noradrenergic system is a likely mechanism for cannabinoid induced analgesia, as the effects are reduced when yohimbine (an alpha-2 adrenoceptor antagonist) is injected into the lumbar region of the spinal cord. The alpha-1 noradrenergic antagonist, phenoxybenzamine, fails to block cannabinoid induced analgesia. Although the cannabinoids do not act at opiate sites, the effects of both drug classes may be mediated through a common descending noradrenergic mechanism. Analgesia produced by injecting morphine in the periaqueductal grey matter is also blocked by intrathecally injected noradrenergic antagonists ().

Rats or mice rendered tolerant to the analgesic effects of morphine show a tolerance to cannabinoid induced analgesia (). Naloxone can decrease the analgesic effects of cannabis in the tail-flick test, the phenylquinone abdominal stretch test, and the hot plate test, but at high doses only. Doses of naloxone known to reverse the analgesic effects of pethidine and morphine in the hot plate and abdominal stretch test do not reverse the analgesic effects of cannabis. After oral administration, THC and morphine produce dose dependent depressions of the passage of a charcoal meal through the gut of mice. THC works out to be about five times less potent than morphine in constipating effect (). These results tend to suggest that cannabinoids do have an involvement with opioid receptors but that the relationship is not straight forward.

It has been reported () that the kappa opioid antagonist, nor-binaltophimine (nor-BNI) effectively blocks the analgesic effects of the cannabinoids, which is compelling evidence for a link between opioid and cannabinoid analgesic systems. The opioid delta antagonist, ICI 174864 and low doses of naloxone are incapable of blocking cannabinoid induced analgesia and there is evidence of cross tolerance between THC and U50488, a kappa agonist. This suggests that only the opioid kappa receptors are involved. Nor-BNI does not affect the behavioural effects of cannabinoids in mice which raises the possibility of developing a cannabinoid derivative with only the analgesic properties. Both THC and morphine analgesic effects are blocked by potassium channel blockers; however the cannabinoids seem to be blocked by calcium-gated potassium channels via apamin, while morphine interacts with ATP-gated potassium channels. It may be that the potassium channel modulation may explain in part the profound cannabinoid/opioid synergism seen in some pain assessment tests. (International Cannabis Research Society Meeting, Keystone, 1992).

Some synergism must also exist in the mechanisms for mu or delta opioid analgesia with cannabinoid analgesia, because intrathecal pre-treatment of mice with sub-effective doses of THC or several other cannabimimetic compounds was able to shift the dose response curve to the left for intrathecal morphine in the tail-flick test; i.e. increase the potency of the morphine (). The exact interaction the cannabinoids have with these neurotransmitters to cause an effect is not clearly known. It is possible that the effects seen are brought about allosterically via the cannabinoid receptor; a mechanism that would allow some sort of selectivity and action only where there was a link between the two types of receptor. It could be by affecting absorption, distribution or fate of a transmitter or even synthesis, storage and release. Some actions of the cannabinoids could be explained by an effect on drug metabolism like cannabidiol which is a known potent inhibitor of drug metabolism (). There is also a report of cannabis increasing the permeability of the blood brain barrier ().

In summary, it is likely that in regard to analgesic effects, the cannabinoids have more than one action on any particular system.


Selections from the book: “Cannabis. The Genus Cannabis”. Edited by David T.Brown. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 1998.