March 2010: A novel process by which cannabinoids alleviate pain has been determined molecularly (Medizinische Hochschule Hannover; Hannover, Germany)

First some background: Chronic pain is often a difficult condition to treat and sometimes even diagnose. Originating as a protective mechanism, pain notifies us when an external stimulus may cause us harm or when something internal start to go awry. However, in certain types of chronic pain and what is referred to as neuropathic pain, this once protective mechanism exhibits functional degeneracy, where its function in the human body is not established. What has been well established however, is the process by which we feel this pain. When peripheral cells are damaged, an inflammatory response ensues, leading to the release of chemicals such as bradykinin, histamine, prostanoids, and tachykinins. These chemicals as well as physical pressure and severe temperatures act on dendritic terminals of nociceptive neurons, mostly activating TRP (transient receptor potential) channels. These TRP channels are a family of stimulus-sensitive non-selective cation channels, thus permeable to sodium, calcium, magnesium, and other positively charged ions. Activation of TRP channels causes a signal to be sent along this nociceptive (pain) neuron, whose cell body resides in the dorsal root ganglion. These cell bodies then relay their signal to a different neuron in the spinal cord. This spinal cord neuron, located in the dorsal horn, also receives input from several other neurons, dictating the level of pain felt and are usually inhibitory. It is well documented that cannabinoids can act in a retrograde fashion at these synapses utilizing CB1 (cannabinoid receptor 1) in order to inhibit the signal coming from the primary afferent neuron (the one that originally sensed the pain). Additionally, it has been established that cannabinoids may act at TRP channels directly, desensitizing them to painful stimuli. However, in recent years, it has emerged that cannabinoids may also act on other parts of the pain pathway.

The new information: Although it has been previously noted that cannabinoids act on different parts of the pain pathway, including glycine receptors, the exact molecular mechanism has not been established. The modulatory inhibitory neurons utilize one of two neurotransmitters to decrease the painful signal coming from the primary afferent neuron: GABA (gamma-aminobutyric acid) and glycine. It is known that cannabinoids somehow act on glycine receptors in order to decrease the sensation of pain. This experiment involved mutating the glycine receptor in specific regions to determine how cannabinoids, specifically cannabidiol, interact with the receptor. By mutating an amino acid in the second transmembrane domain from serine (polar) to isoleucine (nonpolar), cannabidiol had no effect on the receptor. However, in absence of the mutation, cannabidiol caused both co-activation and direct activation of the glycine receptor. Co-activation is also referred to as positive allosteric modulation, where the cannabinoid by itself will not activate the receptor, but in presence of glycine (the receptor agonist), there is an increased intracellular response. Additionally, cannabidiol was shown to directly activate this receptor, causing inhibition of the noxious (painful) signal.

What this means: As mentioned in previous entries, THC (∆9-tetrahydrocannabinol) is not the only cannabinoid found in plants of the Cannabis genus. The remaining cannabinoids all have differing structures, properties, and functions. However, the current pharmaceutical market utilizes only THC containing medication, which cannot fully utilize the benefits of Marijuana. By showing the exact molecular mechanism by which cannabidiol interacts with glycine receptors, another means by which cannabis lead to analgesia has been established.

Foadi, N., et al. “Lack of Positive Allosteric Modulation of Mutated Alpha(1)S267I Glycine Receptors by Cannabinoids.” Naunyn-Schmiedeberg's Archives of Pharmacology. (2010): preprint.

February 2010: Cannabinoids inhibit pain and bone loss induced by bone cancer (The University of Arizona; Tucson, Arizona)

First some background: Malignant bone cancer refers to a number of diverse tumor types, including osteosarcoma, chondrosarcoma, fibrosarcoma, cordoma, and Erwig’s sarcoma. Although the physiological mechanisms leading to tumor formation and malignancy may differ, the main symptoms of most forms of bone cancer are severe pain and bone loss. Thus, in standard treatment regiments for bone cancer, opiates are used in addition to chemotherapy and radiotherapy to abate the pain. However, use of opiates for analgesia has several downsides: physical addiction, high abuse potential, and rapid tolerance to name a few. Additionally, two side effects of chronic opiate use lead to an exacerbation of bone cancer symptoms. The first is pain hypersensitization. When the body is exposed to constant levels of any drug that acts as a receptor agonist, it induces a protective response to maintain its original state. Therefore when exposed to chronic opiate medications, the body reduces expression of opioid receptors, leading to decreased pain inhibition and thus increased sensitivity to pain. The second is hypogonadism. Opiates act on what is known as the hypothalamic-pituitary axis, causing decreased levels of hormone release. One of these hormones is GnRH (gonadotropin releasing hormone). GnRH causes release of two hormones from the anterior pituitary: LH (luteinizing hormone) and FSH (follicle stimulating hormone). These two hormones are responsible for regulating the amount of testosterone in both males and females. Although testosterone is widely known for being the main sex hormone in males, it is also present in lesser amounts in females with a common protective function of maintaining bone density. Thus chronic use of opiate medications will lead to an increased level of bone loss.

The new information: Cannabinoids have been shown to be a more valid alternative for treating bone cancer-mediated pain. The experiment was carried out by inducing bone cancer in mice and performing both behavioral and radiologic image interpretation of symptoms. After confirming the development of cancer, the mice were shown to have experienced both spontaneous and touch-evoked behavioral signs of pain. By administrating cannabinoids to the mice, both the spontaneous and stimulated pain was inhibited. Additionally, a sustained treatment regimen of cannabinoids led to significant reductions in bone loss, manifesting as a decreased likelihood of cancer-induced bone fractures.

What this means: By showing the benefits of utilizing cannabinoids as an alternative analgesic for bone cancer patients, cannabis may be a healthier alternative than opiates in treating pain associated with the cancer. Chronic use of opiates can cause more harm than good, as they often exacerbate the symptoms of bone cancer via patient hypersensitivity to pain and decreased bone mineral density. Cannabinoids on the other hand not only provide a non-physically addictive alternative, but also have been shown to attenuate the bone loss seen in cancer patients.

Lozano, A., et al. “A Cannabinoid 2 Receptor Agonist Attenuates Bone Cancer-induced Pain and Bone Loss.” Life Sciences. 2010: (preprint)