Pain can be classified in one of three ways, according to the signaling pathway involved. Namely, the classifications are nociceptive, inflammatory and neuropathic. Nociceptive pain is the most common and it is high threshold pain activated in response to intense stimuli: when engaged, this pain system overrides most other neural functions. In the same way that nociceptive pain has an adaptive and protective effect, so too does inflammatory pain. When tissue damage has occurred, sensory sensitivity is heightened to discourage physical contact and movement of the affected area: this aids to reduce further risk of damage and promotes recovery. This pain is caused by activation of the immune system, in response to injury or infection. Neuropathic pain is maladaptive: it arises as a result of abnormal functioning of the nervous system and occurs after damage has been sustained to the nervous system, but it can also occur when the nervous system is stimulated in the absence of damage or inflammation stimuli.
When any of these pain pathways are activated, the pain is frequently classed according to its duration: acute or chronic. Acute pain is a short-term pain that lasts less than 3 months and is resolved as the injured tissue is repaired. Chronic pain is defined as lasting 3 to 6 months or longer. Because of the nature of the stimuli, nociceptive pain is classed as acute pain, while inflammatory pain can either be acute or chronic, depending on how long the inflammation and damage take to heal. Neuropathic pain can be acute, but in most cases, it is often chronic, lasting longer than 6months.
When noxious stimuli, such as intense heat are detected by neurons, voltage-gated ion channels are activated to create action potentials that send signals from the periphery to the dorsal horn within the spinal cord and contribute to neurotransmitter release. At the same time, in instances of tissue damage, these signals may also stimulate the release of inflammatory molecules from the neuron as well as other tissues at the site of injury. These proinflammatory molecules, such as histamine, calcitonin-gene related peptide (CGRP), leukotrienes, endocannabinoids, tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β), and a host of others form an “inflammatory soup” that can bind to receptors on the peripheral nociceptor terminal further sensitising them.
One common method to reduce inflammatory pain is through inhibition of the inflammatory response itself. For example, nonsteroidal anti-inflammatories (NSAIDs) act through inhibition of cyclooxygenases (COX-1 and COX-2). Another method for reducing pain is through modulating receptors on nociceptors, directly. Some of these receptors such as opioid, cannabinoid (CB)1 and metabotropic glutamate (mGlu)2/3 receptors decrease responses to noxious stimuli through potentiating ion channels, diminishing the response to pain.
Cannabinoids and Pain Signalling
Cannabinoids reduce pain by activating specific receptors throughout the body. CB1, which is highly expressed within the central nervous system, and CB2, which is highly expressed in cells involved with immune function are the main receptors through which endocannabinoids are thought to work; however, the role of exogenous cannabinoids is only now being elucidated. The phytocannabinoid tetrahydrocannabinol (THC), known to be the major psychoactive component of cannabis, is a direct partial agonist of CB1 andCB2 , while CBD elicits its effects without directly impacting the CB1 or CB2 receptors. However, newer evidence is beginning to emerge that cannabinoids may interact with additional receptors, including additional G-protein coupled receptors, opioid receptors and serotonin (5-HT) receptors. The role these additional non-CB pain receptors play in cannabinoid’s impact on the pain response requires further exploration. Crosstalk among these signalling pathways may impact on the role that cannabinoids play in modulating neuropathic and inflammatory pain.
Cannabinoids and Neuropathic Pain
In animal models, both CB1 and CB2 receptors are upregulated in response to peripheral nerve damage. It is postulated that the beneficial effects of cannabinoid receptor agonists on neuropathic pain may be due to the upregulation of these receptors. Additionally, some animal models of neuropathic pain have shown that CB2 selective agonists effectively reduce pain.
A systematic review of clinical studies on chronic non-cancer pain, including neuropathic pain, concluded that cannabinoids demonstrated a significant analgesic effect, when compared with placebo, with no serious adverse events. The authors concluded that cannabinoids appear to be safe and modestly effective, based on these initial studies, but they recommended that further studies be conducted that investigated specific cannabinoids in a homogeneous population for longer durations of time.
Cannabinoids and Inflammatory Pain
Cannabinoids have been reported to have immunomodulatory as well as anti-inflammatory effects and several animal models have demonstrated a potential role for cannabinoids in the treatment of inflammatory pain, which is a comorbidity of many clinical conditions including arthritis and inflammatory bowel disease. Although the anti-inflammatory mechanisms are not fully understood, a clinical trial examining cannabis-based therapy in rheumatoid arthritis showed a significant reduction in disease activity, suggestive of an anti-inflammatory response. This study also showed an analgesic effect for cannabinoid therapy compared with placebo, with clinically significant improvements in pain on movement, pain at rest, quality of sleep and DAS28 (disease activity score-a measurement of rheumatoid arthritis activity), among others.
Currently, a number of clinical trials are ongoing that are examining the role of phytocannabinoids, as well as synthetic cannabinoids, in the management of different conditions, including osteoarthritis, chronic pain, neuropathic pain, HIV neuropathy and others. Beyond the examination of cannabinoids in different types of pain, additional studies are examining the role of cannabinoids in the inflammatory response, as well as in other chronic conditions.