# Motivation and emotion/Book/2019/Opioid system and human emotion

* Multimedia presentation (3 min)

## Overview

The endogenous opioid system is a neurophysiological system that has an important function in modulating pain response. Due to its broad sites of action, spanning the brain and spinal cord, it also has a wide effect on many other systems, including emotions. The endogenous opioid system consists of three distinct opioid receptors and three families of peptides (Colasanti et al., 2012), which are widely abundant in the central nervous system (CNS). Some of the opioid receptors located in the CNS are found within the limbic system, an important region as it is highly associated with emotions. The binding of opioids to the receptors in the limbic system lead to the alteration of emotions.
Endogenous opioids are naturally produced within the body and used as neurotransmitters (Colasanti et al., 2012). The activation of the endogenous opioids are associated with both pleasant and unpleasant emotions (Nummenmaa & Tuominen, 2018). It is important that we understand what impact the endogenous opioids have on individuals' emotions. Opioids appear to have a vast effect on the major emotions. They have potential to increase happiness, euphoria, and pleasure while decreasing fear, anxiety, and sadness. Additionally, opioids may have influence in anger and aggression.
Given the implications of opioids' effects on emotions, the ability to increase endogenous opioids could be beneficial in combating negative emotions. Numerous lifestyle factors are capable of increasing the production of endogenous opioids and influencing emotions. Such lifestyle factors include exercise, laughter, eating, meditating, acupuncture, and massage.
* Focus questions:
* What are key brain structures relating to emotions?
* What are the main emotions?
* What is the physiology of the opioid system?
* How does the opioid system influence emotions?
* How can lifestyle factors modify endogenous opioids release?

## Opioid system neural structures

There are several brain structures that are important in the functioning of the opioid system. These structures can be divided into several regions. The limbic system and the basal ganglia are both systems of neurons that control emotional behaviour (Le Merrer, Becker, Befort, & Kieffer, 2009). Both of these structures contain many opioid receptors. The dorsal horn of the spinal cord is a region where sensory neurons are found (Le Merrer, et al., 2009). This acts as a way of inhibiting pain signals giving opioids their analgesic effect. Finally, the cerebral cortex also plays an important role in opioid function (Le Merrer, et al., 2009), specifically in the prefrontal cortex region, where the receptors seem to help modulate stress responses (Le Merrer, et al., 2009).

## Physiology of the opioid system

The endogenous opioid system contains three peptides and three receptors, which are abundantly expressed in the emotion circuit of the nervous system (Nummenmaa & Tuominen, 2018). Furthermore, the opioid system modulates a variety of functions related to arousal, motivation, and emotion. In particular, the MOR receptor contributes to emotional processing (Nummenmaa & Tuominen, 2018).

### Families of opioid peptides

The opioid peptides act as neuromodulators to alter how easily the neurons are excited, therefore changing how the neuron releases the neurotransmitters.

#### β-endorphins

β-endorphins are small proteins found in neurons of the limbic system. These bind to the MOR receptors to facilitate their actions. It functions as a pain-relieving agent. They also reduce chronic psychological stress by mediating the release of hormones such as cortisol, adrenocorticotropic hormone (ACTH), and noradrenaline. Additionally, it may also modulate mood.

#### Enkephalins

Enkephalins are a type of protein released in response to pain. Enkephalins are released from the adrenal gland. These primarily bind and activate DOR and MOR receptors in the limbic system and the cerebral cortex regions; where it modulates brain function during stress responses.

#### Dynorphins

Dynorphins are a class of opioid peptides produced in numerous parts of the brain including the limbic system and spinal cord. Dynorphins primarily bind to KOR receptors and have some affinity for MOR and DOR receptors. It has a number of functions: inhibiting oxytocin, acting as an analgesic, and to modulate stress and depressive symptoms.

### Families of opioid receptors

The opioid receptors facilitate the binding of opioid peptides. These receptors are located on specialised cells, enabling opioids to exert their effects. Opioids can only act on cells that possess these receptors.

#### μ (MOR)

μ (MOR) is the most studied class of opioid receptor. It is predominantly located in the dorsal horn of the spinal cord. It is also found in the cerebral cortex and the limbic system; the mammalian emotional circuit. Those found in the dorsal horn inhibit the release of glutamate, thereby inhibiting the type C and type A-delta nociceptors; reducing the experience of pain. The receptors in the cortex and limbic system are involved in the regulation of positive emotional states and pleasure.

#### δ (DOR)

δ (DOR) is a class of opioid receptors found in the cerebral cortex and the limbic system. They are located primarily on sensory neurons where they inhibit the release of neurotransmitters. In the CNS, these receptors contribute to the analgesic effect of the opioids. In the limbic system, these receptors regulate positive emotional states and pleasure.

#### κ (KOR)

κ (KOR) is a class of opioid receptors found in the spinal cord and brainstem. They are also found in the limbic system. Part of the analgesic effect is due to direct inhibition of the pain pathway in the spinal cord. It also plays a direct role in a dysphoric element of stress, critical for modulation of negative emotional states.
Case study part 1: Physiological function of the opioid system
Martha has had a blood test and discovered she had low endogenous opioid levels, especially B-endorphins.
What effect would low B-endorphins have on stress levels?
Answer
B-endorphins mediate the release of important stress hormones such as cortisol. Low levels of these may mean less control over cortisol release and therefore higher levels of circulating stress hormones. This means Martha will experience more stress than normal.
Given that B-Endorphins bind to MOR receptors, what effect would this have on Martha's pain levels?
Answer
MOR receptors facilitate the reduction of pain associated with opioids, a lower level of B-endorphins would mean less pain inhibition and therefore a greater experience of pain. This means Martha would have lower pain tolerance. :

## Basic emotions

Emotions are universal throughout human cultures. Many people would define emotions with terms such as anger, joy, fear, surprise, sadness, and disgust. Emotions can be defined as a psychological state that encompasses feelings, behaviours, and inclinations to act. Hockenbury & Hockenbury (2010) define emotion as a complex psychological state involving three distinct components: a subjective experience, a physiological response, and a behavioural or expressive response. However, emotions are often difficult to define, as there are numerous competing definitions of what emotions are.
Table 3. Common list of emotions :
| Anger | Unpleasant experience. Entails the feeling associated with hostility to another person who you believe has deliberately offended you. |
| Fear | Negative or adverse emotional state. The feeling of threat that occurs when we experience dangerous situations. |
| Disgust | Feeling towards something that an individual find repulsive. For example: spoilt food, dead animals, and toxin substances. Disgust is associated with input from sight, hearing, smell, taste, and touch. The emotion of disgust can be triggered by any of these senses. |
| Sadness | Decline in mood as well as a significant reduction in cognitive and behavioural activity. Can occurs in different situations, for instance, when one loses a valued person or fails to achieve a goal. |
| Joy | The experience of euphoria which makes an individual feel filled with energy and increases confidence and self-esteem. Often felt when an individual achieves goal or experiences superfluous either kindness or affection. |
| Surprise | Normally characterised by a physiological startle response following something unexpected. Positive (pleasant) for example, arriving at work to find that your friends and colleagues have gathered to celebrate your birthday. Negative (unpleasant) for example, a cat jumping out from behind a bush and scaring you as you are walking. |

## Opioid system and the human emotion

The opioid system modulates a variety of functions related to arousal and motivation. Its specific contribution to different basic emotions has remained poorly understood. However, recent research seems to indicate that endogenous opioids are consistently associated with pleasant and unpleasant emotions (Nummenmaa & Tuominen, 2018). It has been shown that MOR and DOR receptors are important in regulating positive emotions, whereas the KOR receptors are important for regulating negative emotions (Watanabe et al., 2013).

### Pleasure, happiness, and euphoria

The release of endogenous opioids can occur with reward consumption and positive moods (Nummenmaa & Tuominen, 2018). The common occurrence of "runner's high", which is a euphoric state triggered by strenuous physical activity has been suggested to occur via endogenous opioids release in several cortical regions (Nummenmaa & Tuominen, 2018). The binding of endogenous opioids to the MOR receptors leads to a cascade of chemical signals throughout the nervous system (Dfarhud, Malmir, & Khanahmadi, 2014). This inhibits the activation of neurons in specific brain regions, resulting in pain reduction and pleasant sensations such as euphoria (Dfarhud, et al., 2014). This specific signalling pathway used also results in an increased production of dopamine (Dfarhud, et al., 2014). This hormone has been associated with a feeling of happiness (Baixauli, 2017).

### Fear and anxiety

The limbic system is vital to emotional responses. The amygdala is of special interest. This region is important in both anxiety and fear learning, as the endogenous opioid system is critical in mediating these responses (Winters et al., 2017). The release of enkephalins occurs in response to stimuli that induce fear, anxiety, and stress (Colasanti, Rabiner, Lingford-Hughes, & Nutt, 2011). Enkephalins activate MOR and DOR receptors in certain brain regions, causing a decrease in aversive response (Colasanti, et al., 2011). Short-term stress also leads to the release of other endogenous opioids, these act via MOR receptors to reduce anxiety and stress (Colasanti, et al., 2011).
Impediment of the opioid system has been shown to be associated with the occurrence of anxiety (Colasanti, et al., 2011). Animal studies indicate that a deficiency in DOR receptors leads to an increase in anxiety (Colasanti, et al., 2011). Additionally, corticotropin-releasing factor, a common hormone released in stressful situations has been linked to the production and release of dynorphins (Land et al., 2008). Dynorphins activate KOR receptors, which have been found to increase anxiety and fear responses (Colasanti et al., 2011). This suggests a close link between anxiety and endogenous opioid deficiency (Sher, 1998). Such a deficiency might diminish an individual's ability to function adequately (Sher, 1998). However, research in this area remains limited; additional evidence is likely needed to fully understand this relationship.

### Sadness and depression

Studies in healthy populations indicate that opioid antagonist triggered dysphoria and increase negative feelings triggered by losses (Nummenmaa & Tuominen, 2018). Transient sadness states also triggered the deactivation of opioid receptors in healthy subjects (Nummenmaa & Tuominen, 2018). Sustained sadness and negative emotions can also cause alteration in endogenous opioids release; known as endogenous opioid system dysregulation (Shenoda, 2014). These characteristics are seen in depressive disorders (Nummenmaa & Tuominen, 2018), however, these presentations are often much more severe. It has also been shown that individuals with depression have an increasing number of MOR receptors (Shenoda, 2014), indicating that this dysregulation is due primarily to the lower concentration of endogenous opioids (Shenoda, 2014). However, studies on individuals experiencing sadness show a significant reduction in MOR receptors, especially in the left cortex (Massaly et al., 2019). Furthermore, modulating the number of KOR receptors appears to be a promising way to prevent sadness (Massaly et al., 2019).

### Anger and aggression

The relationship between anger and endogenous opioids appears to be complex. Individuals with opioid system dysfunction release fewer opioids than normal (Bruehl, Burns, Chung, & Chont, 2009). These individuals tend to have higher levels of anger than those with a normal functioning endogenous opioid system (Bruehl, et al., 2009). The reason behind this is not well understood, but it is believed to be an indirect consequence. This occurs because a reduction in endogenous opioids leads to an increased risk of irritation due to a mixture of pain and anxiety (Bruehl, et al., 2009). Higher levels of irritation cause alteration in mood and an increased risk of anger and aggression (Bruehl, Burns, Chung, & Quartana, 2008).

### Disgust and surprise

Of the six basic emotions, disgust and surprise are the only two that have not been conclusively linked with the endogenous opioid system (Nummenmaa & Tuominen, 2018). This indicates an insufficient amount of research in this area.
Case study Part 2: Emotional response to opioid dysregulation
Martha has been anxious and easy to upset, she has also been experiencing transient states of sadness.
Why is Martha feeling anxious?
Answer
Endogenous opioids are important in buffering and reducing anxiety. With lower levels of endogenous opioids, Martha has higher activity within the amygdala. This increases the subjective experience of anxiety.
Why is Martha less able to control her emotions?
Answer
Because Martha has lower endogenous opioids it is likely that she has a lower pain tolerance. This means that she is likely to become irritated easier than she normally would.
Why is Martha experiencing states of sadness?
Answer
Lower levels of endogenous opioids mean less activation of opioid receptors. This reduces the feeling of euphoria and pleasure and increases the feelings of sadness. :

## Ways to increase endogenous opioids

The ability to alter levels of circulating endogenous opioids can have a significant effect on emotions. Being able to facilitate this change with simple, modifiable lifestyle factors may provide a cost-effective and accessible way for individuals to modify their emotional state. Several lifestyle factors have been shown to increase the level of endorphins and other endogenous opioids. These factors are highly associated with changes in emotions and moods.

### Laughter

Laughter is universally seen as a positive expression (Manninen et al., 2017). It has been shown that laughter stimulates the release of endogenous opioids in the brain circuits involved in reward and arousal (Manninen, et al., 2017; Nummenmaa & Tuominen, 2018). The stimulation increases pleasant feelings, supporting the creation and conservation of social bonds (Manninen, et al., 2017). This is an important factor in interpersonal communication, helping foster and strengthen relationships (Manninen, et al., 2017). Additionally, laughter is an advantageous mechanism to cope against stressful situations (Manninen, et al., 2017).

### Exercise

Exercise is an important means for altering mood and enhancing an individual’s health and well-being (Arida et al., 2015). The exact mechanisms for these effects are not fully established. However, research indicates that the endogenous opioid system is at least one mechanisms that contributes to these effects (Saanijoki et al., 2014). Studies show that exercise both increases the number of opioid receptors and also stimulates the release of endogenous opioids (Leuenberger, 2006; Nummenmaa & Tuominen, 2018; Saanijoki, et al., 2014). This mechanism is used to explain the “runner’s-high”, which is the common term used to describe the positive effects that exercise has on mood (Leuenberger, 2006). Recent research has shown that endogenous opioids increase both in response to acute and chronic exercise (Lima, Abner, & Sluka, 2017). In addition to the direct evidence that endogenous opioids lead to euphoria, this strongly indicates that exercise may improve mood (Lima, et al., 2017).

### Eating

Studies on animal populations indicate that the consumption of food leads to an increase in the release of endogenous opioids (Tuulari et al., 2017). This research indicated that the magnitude of release was not influenced by how pleasurable the food was (Tuulari, et al., 2017). However, this finding has been contested, with some authors suggesting chocolate increases endogenous opioids release due to its pleasing taste (Nehlig, 2013). Further research has illustrated the consumption of spicy food may lead to an increase in the release of endogenous opioids (Park et al., 2017). This occurs due to the pain caused by the spiciness of the food, leading to an increase in endogenous opioids released to counteract the pain (Park, et al., 2017). It has been hypothesised that excessive eating may overstimulate the endogenous opioid system, therefore leading to obesity (Tuulari, et al., 2017).

### Meditation

There are several well-known meditation practices such as mindfulness, kundalini, and transcendental meditation (Krishnakumar, Hamblin, & Lakshmanan, 2015). Engaging in at least 20 minutes to one hour of meditation leads to the release of endorphins (Harte, Eifert, & Smith, 1995). This results in happiness, calmness, and feeling of content, leading to an elevation of positive mood (Harte, et al., 1995). Meditation is most often seen as a form of relaxation therapy that can improve the level of anxiety and stress (Krishnakumar, et al., 2015).
Case study 3: Lifestyle factors to modulate endorphin levels
Martha would rather not take medicine to help regulate her endorphin levels. However, she is more than happy to alter her lifestyle.
Suggest three ways Martha can boost her endorphin levels by changing her lifestyle. For each suggestion explain how it works and why is it a good choice for Martha.
Answer
Laughter – stimulates the release of the endogenous opioids, which increases the feelings of euphoria and pleasure. This is a good choice because in addition to the opioid release it can help foster bonding and relationship.
Exercise – helps enhance moods by several mechanisms, one of these is increase endogenous opioid release. This is a good choice because exercise is important to maintain health and well-being.
Meditation – helps release endorphins, which result in happiness, calmness, and feeling of content. This is a good choice it is often seen as a form of relaxation therapy and has been shown to improve the level of anxiety and stress.
Eating – increases endogenous opioids and improves mood. This could be due to palatability of the food or due to the spiciness of food triggering a pain response. This choice is good if Martha modifies her diet in a healthy way, otherwise, if her dietary modification is unhealthy it might increase the risk of chronic diseases and obesity. :

## Conclusion

The opioid system plays an important role in regulating physiological functions within the human body. Endogenous opioids have a wide range of functions. This is likely because opioid receptors are found in numerous brain regions. One of the major roles is to decrease the perception of pain, this physiological response, in and of itself, likely helps modulate emotions and facilitate positive mood. Additionally, because it is a major part of the limbic system, the opioid system can modulate emotions directly. The emotional responses tend to be positive in nature.
Endogenous opioids can both reduce negative emotions and increase positive emotions. They can facilitate a reduction in sadness and depression as well as a buffer against the negative effects of stress and anxiety. This helps reduce the perception of negative mood and promote health and well-being. In addition, endogenous opioids can enhance pleasure, happiness, and euphoria. The exact cause for the occurrence is not well understood, with two theories attempting to explain why. The enhancement of dopamine release via the endogenous opioid signalling pathway may be one reason for the increase in happiness. The other factor involved is the pain-relieving effect of the endogenous opioids. This pain relief likely reduces negative mood, making the individual feel better. Influencing endorphin release is a highly promising mechanism for altering mood.
Many lifestyle factors have been shown to promote the release of endogenous opioids. These factors have also been shown to be effective at altering emotions and mood. Modifying life factors could be a cost-effective tool for combating conditions such as depression, anxiety, and potentially chronic pain pathologies.