How do we sense pain?

If you were to touch a hot stove, bang your foot against a table, or accidentally touch battery acid, you will most likely withdraw your hand rapidly and experience pain. But why is this?

Distributed throughout our body are nerve endings with specialized pain receptors, called nociceptors. These are activated by various stimuli that indicate or have potential to cause tissue injury, including:

• Mechanical stimulation (e.g. excessive pressure, stretching, cutting)
• Thermal stimulation (e.g. intense heat or cold)
• Chemical stimulation (e.g. acid pH, irritants, capsaicin in chilli peppers).

For example, if you were to prick your hand on a cactus (see diagram below), this would activate mechanical nociceptors on nerve endings in your hand.

Activation of nociceptors then triggers an electrical signal, which travels down special sensory nerve fibres known as Aδ and C fibres. These conduct information about the pain to our spinal cord (specifically a part of the spinal cord known as the dorsal horn).

Once in the spinal cord, the nerve fibres make connections or ‘synapses’ with other neurons. Some of these may be interneurons or relay neurons, which connect to motor neurons that activate muscles.

In the cactus example, for instance, the pain signal from pricking your hand will activate motor neurons that cause various muscles to contract, causing you to quickly remove your hand. This is known as a reflex arc (see diagram below).

For us to experience pain, however, the pain signal needs to be sent up the spinal cord to higher parts of the brain. As shown in the diagram below, the pain signal travels up the spinal cord to the brainstem and then onto part of the brain known as the thalamus.

The thalamus acts as a kind of “relay station” for the pain signal. It forwards the pain signal to lots of different parts of the cortex, which gives rise to the experience or perception of pain.

It is important to note that we can still sense and transmit pain signals (known as nociception) without the subjective experience of pain. We feel pain only when the pain signal is relayed to the cortex.

Relaying the pain signal to parts of the cortex also allows us to register important information about the painful stimulus. For example, the thalamus projects to emotional centres in the brain, causing the pain to have an unpleasant character, as well as memory networks in the cortex, allowing us to learn to avoid the painful stimulus in the future.

It’s worth noting that the brain, as well as receiving pain signals, can also send information down to the spinal cord, which can either enhance or dampen incoming pain signals. This is known as our descending pain modulatory system and it plays an important role in shaping our experience of pain.

KEY POINTS

• We have nerve endings with pain receptors (nociceptors) that are activated by mechanical, thermal, and chemical tissue injury.
• Pain signals are first transmitted to the spinal cord and then upwards towards the brain.
• We experience pain when a pain signal reaches higher areas in the brain (known as the cortex).
• The brain has descending projections that can modify incoming pain signals in the spinal cord, which can alter how we experience pain.

What is anandamide?

Anandamide (AEA) is one of the key signalling molecules in our endocannabinoid system: - a widespread nerve-signalling system found in the brain, spinal cord, peripheral nervous system, and digestive tract.

The endocannabinoid system plays a role in several different processes in the body, including regulation of mood, appetite, memory, and inflammation. It also affects how we process and experience pain.

You can read more about the different components of the endocannabinoid system in the Compulsive overeating (FAAH) trait article.

To recap briefly, the endocannabinoid system includes specialized receptors, known as cannabinoid receptors, that are found on the surface of nerves and other cells in the body.

There are two main types of cannabinoid receptors: CB1, found mainly on neurons in the brain and spinal cord; and CB2, found mainly on cells of the immune system.

Anandamide is what is known as an ‘endogenous cannabinoid’ or endocannabinoid. It is a molecule, produced naturally by nerve cells, that binds to and activates cannabinoid receptors.

(Note that endocannabinoids are different from phytocannabinoids, such as THC [tetrahydrocannabinol] or CBD [cannabidiol], which are produced by the cannabis plant and are not naturally made by our body.)

When anandamide binds to the CB1 receptor on neurons in the brain and spinal cord, it inhibit the release of neurotransmitters and changes nerve activity. By changing the activity of neurons that carry and modulate pain signals, anandamide can affect our experience of pain.

KEY POINTS

• The endocannabinoid system is a widespread nerve-signalling system that affects several processes, including pain perception.
• Anandamide (AEA) is a key signalling molecule in our endocannabinoid system.
• Anandamide is produced naturally in the body by nerve cells.
• When anandamide binds to cannabinoid receptors on nerves in the brain and spinal cord, it changes nerve activity.
• Anandamide can alter our experience of pain by altering nerve activity in neurons that signal pain.

How does anandamide affect pain sensation?

If you’ve ever gone for a run, you may have experienced the fabled “runner’s high” - a feeling of euphoria, coupled with a reduction in pain sensation. Studies suggest that this pain-reducing effect, known as exercise-induced hypoalgesia, is partly due to the release of anandamide in the brain and spinal cord during physical activity.

Lots of other studies suggest that anandamide

As explained in the previous section, anandamide binds to and activates cannabinoid receptors, particularly CB1 receptors, which alters the activity of nerves. In this respect, there are three major ways by which anandamide reduces pain sensation:

• It inhibits incoming pain signals from peripheral nerves.
• It inhibits pain signals ascending up neurons in the spinal cord towards the brain.
• It activates our descending pain modulatory system, which dampens down pain signals.

In addition to the above, anandamide can alter the activity of brain circuits in the cortex that change how we perceive and subjectively experience pain.

Source: Maldonado, R., Baños, J. E., & Cabañero, D. (2016). The endocannabinoid system and neuropathic pain. Pain, 157, S23-S32.

Part of anandamide's pain-reducing effects may also be due to its interaction with the body's endogenous opioid system - a widespread nerve-signalling system involved in the control of pain. This system is activated by internal (e.g. endorphins) and external (e.g. morphine) opiates.

KEY POINTS

• Anandamide acts to reduce feelings of pain.
• Anandamide inhibitis incoming pain signals in peripheral nerves and the spinal cord.
• Anandamide activates descending pathways that dampen down pain signals.
• Anandamide interacts with our opioid system to reduce feelings of pain.

What is FAAH?

FAAH stands for fatty acid amino hydrolase. It is an enzyme responsible for breaking down anandamide (AEA) in the central nervous system.

By breaking it down, FAAH terminates the action of anandamide on CB1 receptors and prevents further changes in nerve activity.

As the main pathway for breaking down anandamide, changes in the activity of FAAH can significantly influence levels of anandamide within the endocannabinoid system. This, in turn, can influence how effectively we suppress pain signals and how we experience pain.

KEY POINTS

• FAAH is the main enzyme that breaks down anandamide (AEA)
• FAAH activity significantly affects your levels of anandamide in the endocannabinoid system.

How do FAAH gene variants affect anandamide levels?

The FAAH enzyme is encoded by your FAAH gene.

A SNP (Single Nucleotide Polymorphism) within the FAAH gene, designated rs324420, causes a change in the DNA code from the letter ‘C’ to the letter ‘A’. This gives rise to two different FAAH gene variants or ‘alleles’ – the ‘C’ allele and the ‘A’ allele.

The ‘A’ allele codes for an FAAH enzyme that is more readily degraded. Consequently, this leads to lower enzyme levels and therefore lower overall activity of the FAAH enzyme.  Due to this reduced enzyme activity, people with the ‘A’ allele of the FAAH gene break down anandamide (AEA) less effectively, resulting in higher anandamide levels in the central nervous system and circulating in the bloodstream.

Elevated anandamide (AEA) levels may, in turn, cause a greater degree of activation of CB1 receptors on neurons involved in the transmission of pain signals. This may lead to enhanced suppression of pain signals and lower pain sensitivity.

KEY POINTS

• The rs324420 SNP creates two different FAAH gene variants: ‘A’ and ‘C’ alleles.
• The ‘A’ allele is associated with lower FAAH activity and higher anandamide levels.
• People who carry the ‘A’ allele (i.e. AA or AC genotypes) have higher anandamide levels.
• Higher anandamide levels are linked to greater suppression of pain signals and reduced pain sensitivity.
  

How do FAAH gene variants affect pain sensitivity?

As explained in the previous section, the ‘A’ allele of the FAAH gene (rs324420) is linked to higher levels of anandamide, which can influence how we experience pain.

Some studies have shown that people who inherit two copies of the ‘A’ allele (i.e. people who have the AA genotype) have lower pain sensitivity. To clarify, lower pain sensitivity means that a person subjectively experiences less pain for a mechanical, thermal, or chemical stimulus of a given intensity.

On this note, researchers examined the cold pain sensitivity of 900 women before a surgical procedure for breast cancer. The subjects immersed their hands in cold water (between 2-4 C) and then, at regular intervals, rated their feelings of pain on a scale from 0 – 10 (with 0 being ‘no pain’ and ‘10’ being ‘worst pain imaginable’).

Those with the ‘AA’ genotype reported significantly lower average pain ratings (7.3 after 30 seconds immersion in cold water) compared to those with AC (8.5) and CC (8.2) genotypes.

Furthermore, people with the AA genotype were found to have a higher pain tolerance – the maximum level of pain someone can tolerate. In the study, pain tolerance was assessed by measuring the maximum amount of time subjects could keep their hands immersed in cold water.

Subjects with the AA genotype could withstand, on average, 54.6 seconds immersion in cold water, which was significantly longer than those with AC (43.4 seconds) and CC (47.5 seconds) genotypes.

The same study also looked at subjects’ use of oxycodone, an opioid painkiller medication, after surgery. As may be expected, people with AA genotype, who demonstrated lower pain sensitivity / higher pain tolerance, required less oxycodone in the first 20 hours following surgery. It’s important to note, however, that this was relationship was not statistically significant.

In another neuroimaging study, healthy subjects were administered a high-concentration saline solution, which causes a painful, stinging sensation, and were asked to rate their experience of pain. Before the pain trial, some subjects were given an intravenous placebo (they were injected with a low-concentration saline solution), which they were told was a pain-killing medication.

The researchers found that those with the AA genotype had significantly greater reductions in pain ratings in response to the placebo. Furthermore, neuroimaging revealed that administration of the placebo was associated with greater activation of the brain’s endogenous opioid system. It is therefore possible that higher anandamide levels in people with the AA genotype leads to reduced pain sensitivity through interaction with the brain’s opioid system.

KEY POINTS

• People with the AA genotype have been shown to have reduced pain sensitivity.
• The AA genotype has been linked to greater cold pain tolerance.
• The AA genotype has been linked to greater pain reductions in response to an intravenous placebo drug.

Your Pain Sensitivity (FAAH) trait

Your Pain sensitivity (FAAH) trait will classify you into one of two groups based on variants of your FAAH gene created by the rs324420 SNP:

• Reduced Pain Sensitivity: you have the AA genotype linked to higher anandamide levels and reduced pain sensitivity / greater pain tolerance.

• Average Pain Sensitivity: you have either the AC or CC genotype, both of which are not linked to reduced pain sensitivity.

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