NEW YORK—“Up until about 10 years ago, we had no clear vision about what marijuana does in the brain,” Billy R. Martin, PhD, professor of pharmacology, Medical College of Virginia, said at the Third Conference on Pain Management and Chemical Dependency.
In the last 10 years, he said, the analgesic properties of marijuana and its main psychoactive derivative, delta-THC (tetrahydrocannabinol), have received considerable attention. The result is the opening of new doors into the understanding of the cannabinoids as adjuvants to opioid therapy, if not as analgesic agents in their own right.
While the analgesic efficacy of THC is comparable to that of codeine(Drug information on codeine), its side effects, which include sedation and dysphoria, remain problematic. “Most patients who suffer from cancer-related pain do not like the psychoactive effects of these compounds,” Dr. Martin said.
He noted that when THC is administered intravenously, it is actually more potent than morphine(Drug information on morphine). This has stimulated continued interest in cannabinoids in chronic pain, and has prompted an intensive search for cannabinoid derivatives devoid of psychotomimetic properties.
The search has resulted in the development of bicyclic derivatives and aminoalkylindoles, both novel classes of highly potent analgesics. These analgesics were crucial in the elucidation of a cannabinoid endogenous system, which includes G-protein-coupled cannabinoid receptors—CB1 in the central nervous system and CB2 in the peripheral nervous system.
“There is an endogenous biologic system that we can now use to determine whether or not cannabinoids work to alleviate any type of pathologic disorder, including pain,” Dr. Martin said.
Relationship to Opioids
Researchers are still striving to gain a comprehensive understanding of how the endogenous cannabinoid system and other neurochemical systems interact and relate to each other. While researchers are sure that the endogenous cannabinoid system plays a specific role in pain modulation, and they know there is a direct relationship between opioid and cannabinoid systems, opioids do not bind to the same receptors as cannabinoids, Dr. Martin said.
“The interaction must be occurring at some final pathway,” he said. Cannabinoids and opioids are known to potentiate each other’s analgesic effects through cannabinoid-stimulated release of dynorphin, a spinal cord peptide whose expression increases after injury to peripheral nerves.
Small modifications to the THC molecule have allowed the development of new compounds that are very similar to the opioid agonists and antagonists. “This approach will provide us with new treatment strategies for opioids,” Dr. Martin commented.
Cannabinoids produce antinociception through both spinal and supraspinal sites of action in the CNS. The supraspinal site appears to activate a descending nor-adrenergic system. In the brain, CB1 receptors in PAG (periaqueductal grey) may be a critical area for cannabinoid-induced antinociception.
THC and its related analogs in comparable doses produce a wide range of effects, Dr. Martin said. Researchers have looked into four measures: spontaneous activity, body temperature, acute analgesia, and catalepsy.
Analysis has shown an excellent correlation between receptor binding of CB1 and pharmacologic activity for all four measures, indicating that this receptor is associated with pain mechanisms.
An exciting advance in the field, Dr. Martin noted, was the discovery of an arachidonic acid derivative, anandamide, which occurs naturally in the brain and binds to the CB1 receptor. It may tonically modulate nociception. As an endogenous cannabinoid ligand, its structure is not similar to THC. It does, however, produce effects very similar but not identical to THC in rats.
“This is an exciting development,” Dr. Martin said, “because the role of arachidonic acid and its metabolites is well known in pain mediation and inflammation.” This relationship has fueled intensive efforts into the understanding and regulation of arachidonic acid’s synthesis, cellular uptake, storage, release, and its possible role as a neurotransmitter.
Cannabinoids are known to block acute nociceptive pain and are effective in some types of neuropathic pain. THC produces antinociception in an arthritic nociceptive model induced in rats, and another derivative blocks hyperalgesia and allodynia following chronic constriction injury of the sciatic nerve in rats. While peripheral CB1 and CB2 receptors mediate antinociception, spinal sites of action have been found to involve alpha-2 receptors.
The involvement of PAG in cannabinoid-induced antinociception has been a key focus. It is an important CNS area for antinociception, containing a higher concentration of cannabinoid receptors than other brainstem areas. Also, stimulation activates descending monoaminergic spinal pain inhibitory systems, and intrathecal yohimbine (an alpha-2-adrenergic blocker) attenuates antino-ciceptive effects of THC administered intravenously.
Dr. Martin concluded, “Manipulation of the endogenous cannabinoid system by altering anandamide or, on the other hand, manipulation of THC derivatives, promises to show that cannabinoids are important adjuvants to opioid therapy, if not important analgesic agents in their own right.
The only cannabinoid-based drug on the market, Marinol, is THC in pill form. It is approved for nausea and vomiting associated with chemotherapy and for AIDS-associated anorexia and weight loss. Look for a full report on the IOM findings next month.]
Editors’ Note: The Institution of Medicine has released a report entitled Marijuana and Medicine: Assessing the Science Base, which found that “marijuana’s active components are potentially effective in treating pain, nausea, the anorexia of AIDS wasting, and other symptoms, and should be tested rigorously in clinical trials.” The report notes that “knowledge of cannabinoid biology has progressed rapidly in recent years, pointing the way to new, potentially promising avenues for drug development.”
