Endocannabinoid System

The Role of the Endocannabinoid System in Thermoregulation

The organ that is primarily responsible for regulating body temperature is about the size of an almond. It is called the hypothalamus. Scientific research has discovered that there are CB1 receptors located within this small but powerful part of the brain, so what exactly is the role of the Endocannabinoid System in thermoregulation?

What is thermoregulation?

Thermoregulation is the process of maintaining the physiological temperature of warm-blooded animals. Every animal has a balanced temperature range that they must stay within to ensure normal functioning; for example, to ensure that enzymes, non-enzymatic proteins, and cell membranes do not denature.

Without a means of thermoregulation, the biological system would fail to function properly, nerves would be unable to signal one another (hundreds of other processes would also become unstable as well – this is just one of the fatal examples), and life would become unsustainable. For humans, the average body temperature is 98.6℉ with a normal range between 97℉ and 99℉. If a person has a body temperature over 100.4℉ this means this person has a fever, possibly caused by an infection or illness.

How does thermoregulation work?

The basic process of thermoregulation is as follows. It begins with an external stimulus; a change in the temperature of the external environment, which causes the body’s temperature to rise or fall accordingly.

Proteins known as TRPV receptors are located in specialized nerve endings, in both the skin and the brain (hypothalamus), which detect changes in their ambient temperature. If there is a drop in temperature, then a receptor will register this change, send a signal to the control center – the hypothalamus – and cause an appropriate response to return body temperature to the healthy range.

Thermoregulation in the skin

In the skin, thermoreceptors with TRPV channels detect changes in the temperature of the skin in which they are embedded, not the temperature of an object touching the skin. This is why it takes around a second for heat to be felt; the skin temperature must rise for the nerves to detect this change. Thermoreception in the skin is useful for protecting against noxious heat or cold which can cause local damage to tissue in the form of a burn. It is also useful for sensing when hypo- or hyperthermia may be probable due to noxious relative ambient temperature, i.e. a hot summer day or a freezing winter night.

Thermoregulation in the brain

In the brain, a nucleus located within the hypothalamus is capable of detecting the temperature of the blood passing through it as a measure of core body temperature as opposed to relative ambient temperature. TRPV are able to detect temperature because their structure changes with temperature. Their structure at the healthy bodily temperature of 98.6 is called the set point.

When the temperature of the protein (and therefore the temperature of the skin or blood near it) is warmer or colder than the set point, the receptor’s shape changes and it releases a signal.

When the temperature rises, heat-loss mode is activated and the body begins to sweat in order to release heat through evaporation. If the temperature has fallen, skeletal muscles compensate via shivering to produce excess heat, and smooth muscle around capillary blood vessels constrict to reduce blood flow to the periphery and keep the internal organs warmer.

What is the Role of the Endocannabinoid System in thermoregulation?

It is well-established that small doses of cannabinoids produce hyperthermic effects in the bodies of mammals. At higher doses, cannabinoids elicit hypothermia. It is hypothesized that because cannabinoid agonist activity inhibits adenylyl cyclase, this reduces the overall energy output of the organism, reducing heat produced as a byproduct of respiration.

Scott M. Rawls & Khalid Benamar stated in their research paper that the preoptic anterior hypothalamus was a region of high interest for cannabinoid administration. When a dosage of cannabinoid agonists were injected into the preoptic anterior hypothalamus region, rapid and dose-dependent hypothermia resulted.

Rats reacted the same way upon injection of cannabinoid agonists, regardless of the type of cannabinoid agonist given. Because rats without CB1 receptors failed to experience a hypothermic response to the cannabinoid injection, scientists believe that CB1 receptors must have a principal role in thermoregulation.  

The hypothermic response observed in lab rats was the same even when three different cannabinoid agonists were used:  Δ9-THC, WIN 55212-2, and HU-210. This implies that the response was independent of the chemical structure of the cannabinoid. Instead, the magnitude of the hypothermic response was dependent on the route of administration, with the strongest response coming after systemic administration to the preoptic anterior hypothalamus.

Paracetamol, the active ingredient in Tylenol, is a popular fever reducer. However, the mechanism of action of paracetamol remained unknown for nearly 60 years. Recently, it was discovered that an active metabolite of paracetamol – AM-404 – is a partial cannabinoid CB1 receptor.

This is now considered to be the primary mechanism of action of Tylenol, as it accounts for all of the apparent effects of paracetamol. Furthermore, it establishes an entirely new class of cannabinoid molecules which exert their therapeutic effect on targets classically considered to compose the endocannabinoid system (i.e., CB1 receptors).

Can endocannabinoid deficiency affect thermoregulation?

It is not difficult to hypothesize how the endocannabinoid system may become deficient in the hypothalamus, and if such a thing were to occur, then the results may be similar to the following. Scott M. Rawls & Khalid Benamar observed that rats lacking CB1 receptors did not experience cannabinoid-induced hypothermia. It has been thought that fever occurs as a mechanism of the immune system to reduce the volume of an infection.

However, in light of the recent discovery of the role of the endocannabinoid system both in the immune system and in the thermoregulatory system of mammals, it is reasonable to suggest that hyperactivity of the immune system during an infection could result indirectly in dysfunction of the endocannabinoid system with respect to its role in thermoregulation, due to increased ratio of prostaglandins to endocannabinoids, or some other inevitable result of the intertwined nature of the endocannabinoid system, the immune system, and their shared signaling machinery.