Human mutations show that endocannabinoids reduce pain and anxiety
This is the fourth in a series of articles about the neuroscience of cannabis and the endocannabinoid system. The previous articles are:
The blessing of feeling no pain
The powerful analgesia produced by endocannabinoids is illustrated by the story of Jo Cameron. She is a Scottish woman who at 66 years of age went to the hospital for hand surgery for osteoarthritis (Habib et al., 2019). Although this type of surgery is particularly painful, she only had to take paracetamol to deal with the post-surgery pain.
In fact, that was not the only time that she had proven to be insensitive to pain.
During all her life, she had surgeries and dental procedures without requiring analgesia. She had always suffered numerous cuts and burns without experiencing pain. Sometimes, when she burned herself, she smelled her burning flesh before feeling any pain. Strangely, her wounds often healed quickly and left no scars.
In addition, she didn’t experience much anxiety and depression, and never had a panic attack.
However, her memory was not very good. She often forgot what she was saying mid-sentence. Finding keys and other things was always a challenge.
The curse of feeling no pain
There are other people who are unable to feel pain. However, unlike Jo Cameron, who lived a long a happy life, their cases are quite tragic.
Since they cannot feel pain any at all, they don’t realize when they harm themselves, so they constantly suffer dangerous wounds. Most of them die young.
It seems that Jo Cameron, instead was able to feel enough pain to make her aware when she was hurting herself.
The most common cause for the total lack of pain is a mutation in the Scn9 gene that disables Nav1.7 sodium channels (Cox et al., 2006).
Oddly, the propagation of action potentials in pain-sensing fibers is not compromised in mice genetically engineered to delete Nav1.7 channels (MacDonald et al., 2021). And yet, these mice are completely insensitive to pain.
What really happens when Nav1.7 are eliminated in these mice is that the first synapse of pain sensory fibers with spinal cord neurons ceases to function, because it becomes strongly inhibited by µ-opioid receptors. Evidence of this is that the opioid receptor antagonist naloxone restores pain in mice lacking the Nav1.7 channels. Naloxone also brought pain back in people with the mutation in the Scn9 gene that makes them insensitive to pain.
Compounds that block Nav1.7 channels are currently being developed as analgesics.
The mutations that made Jo Cameron to feel less pain and anxiety
However, the loss of pain in Jo Cameron was different from that in people lacking Nav1.7 channels. In her, the lack of pain was not complete, so she didn’t suffer the horrible wounds associated with the loss of Nav1.7 channels.
What she had were two mutations that rendered ineffective the enzyme fatty acid amide hydrolase (FAAH) that degrades the endocannabinoid anandamide (Habib et al., 2019).
Her first mutation reduces the activity of FAAH. There are other people with this mutation, but they only have a small decrease in pain sensitivity and anxiety.
Her second mutation was much more complex. It was on a pseudogene, a portion of DNA that doesn’t get translated into protein. This particular pseudogene was named FAAH-OUT. It is transcribed into a long non-coding RNA that appears to be necessary for the functioning of the FAAH enzyme.
Hence, the mutation in FAAH-OUT combined with the most common mutation in the FAAH gene rendered FAAH completely non-functional in Jo Cameron. This caused her brain to be unable to quickly degrade anandamide, so it activated her CB1 and CB2 cannabinoid receptors for longer times. Indeed, concentrations of anandamide in her blood were increased by 70%. Her levels of 2-archidonylglycerol (2-AG), the other endocannabinoid, were normal.
The case of Jo Cameron illustrates how anandamide produces a strong inhibition of pain, anxiety and depression.
One is tempted to say that she spent her entire life high on her own endocannabinoids. However, this is not completely true because the effects of endocannabinoids are not entirely similar to those of THC.
References
Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894-898.
Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DLH, Srivastava D, Cox JJ (2019) Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br J Anaesth 123:e249-e253.
MacDonald DI, Sikandar S, Weiss J, Pyrski M, Luiz AP, Millet Q, Emery EC, Mancini F, Iannetti GD, Alles SRA, Arcangeletti M, Zhao J, Cox JJ, Brownstone RM, Zufall F, Wood JN (2021) A central mechanism of analgesia in mice and humans lacking the sodium channel Na(V)1.7. Neuron 109:1497-1512.e1496.
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