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Pain can be distinguished as either acute or chronic. Acute pain is the body’s response to a single event such as tissue damage. The neurophysiology of acute pain is well understood and most occurrences are resolved with the discontinuation of the stimulus.

Chronic pain continues relentlessly and is often attributed to impairment of the nervous system. This type of chronic pain results from either unresolved disease causing nerve stimulation (nociceptive pain) or from physiological changes within the nervous system (neuropathic pain). Chronic pain is often debilitating to sufferers and resistant to traditional pharmaceuticals.


Pain Physiology


Nociceptors are specialised receptors responsible for detection of noxious stimuli and translating these sensations into electrical signals, which are then relayed to the brain. These receptors are triggered by physical (bumps or knocks), thermal (hot or cold) or chemical (inflammatory mediators or corrosive agents) stimuli. Once a noxious stimulus has been detected primary afferent fibres relay the signal into the spinal cord where the secondary afferent fibres transmit these signals higher to the brain which in turn, creates the sensation of pain.

Pain Inhibition
The endogenous system responsible for nociceptive pain control is termed the descending pathway. The descending pathway is the nociceptive modulatory system, which, when activated either chemically or electrically produces an analgesic effect. Important sections of this pathway include the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM). Generally, these sections have been well characterised as fundamental in the pain cascade.

This image is a simplification for website aesthetics only. For more information please refer to the clinical studies referenced below.


Endocannabinoid System and Pain

Cannabinoid receptors, specifically CB1, are well distributed throughout the endogenous pain modulation pathway. Key areas in pain transmission include the periaqueductal gray matter, rostral ventromedial medulla and the primary afferent neurons. Studies have shown that up-regulation of the endocannabinoid system produces an analgesic effect.

Primary Afferent Neurons
Studies in mice in which CB1 receptors were removed from primary afferent nociceptive sensors showed an increased sensitivity to noxious stimuli. From this, the researchers proposed that CB1 receptors are involved in primary pain transmission from the periphery to the spine. Furthermore, these animals were found to be hypersensitive to noxious stimuli, which supports the hypothesis. Transient potential vanilloid receptors are also found on the primary afferent neurons and have been suggested to work synergistically with cannabinoid receptors to reduce pain transmission when activated by cannabinoids.

Periaqueductal Gray Matter
The PAG is considered the relay center for pain in the brain. PAG electrical stimulation is well known to produce analgesic effects in rats. CB1 receptors are densely concentrated through the PAG. Studies have shown that injection of cannabinoids into the PAG produce a similar analgesic effect that can be reversed by a CB1 antagonist. Analgesic effect is produced in PAG via transmission of pain signals to the descending nociceptive pathway. The degree to which pain is modulated in this area of the brain is determined by GABA and glutamate excitation. Glutamate stimulation is know to have an analgesic effect, conversely GABA excitation is inhibitory to the descending antinociceptive pathway. Traditional opioid analgesics produce a stronger antinociceptive effect than cannabinoids. Opioid treatment results in downregulation of spinal opioid receptors, whereas CB1 receptors are unregulated in neuropathic pain.

Rostral Ventromedial Medulla
RVM contains two cell types which are known to influence the descending antinociceptive pathway. ON cells are associated with increased pain signaling. OFF cells are associated with the analgesic effect. Cannabinoid receptor agonists have been shown to reduce the ON cell burst and decrease the OFF cell pause.

Pertinent Studies:
Fine, P. G., & Rosenfeld, M. J. (2013). The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides medical journal, 4(4).
Johnson, J. R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E. D., Potts, R., & Fallon, M. T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: CBD extract and THC extract in patients with intractable cancer-related pain.Journal of pain and symptom management, 39(2), 167-179.
Malik, Z., Baik, D., & Schey, R. (2015). The Role of Cannabinoids in Regulation of Nausea and Vomiting, and Visceral Pain. Current gastroenterology reports,17(2), 1-9.
Manzanares, J., Julian, M. D., & Carrascosa, A. (2006). Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Current neuropharmacology, 4(3), 239.
Pertwee, R. G. (2001). Cannabinoid receptors and pain. Progress in neurobiology, 63(5), 569-611.
Rog, D. J., Nurmikko, T. J., & Young, C. A. (2007). Oromucosal  9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clinical therapeutics, 29(9), 2068-2079.