Enkephalins are natural compounds found within the body that regulate mood and the perception of pain. These molecules form a central component of the body’s intrinsic pharmacy, acting as internal pain relievers and modulators of emotional states. Understanding how enkephalins work provides insight into the body’s mechanisms for maintaining balance during physical or psychological stress. This system helps an organism cope with challenging situations by altering sensation and emotional response.
What Enkephalins Are
Enkephalins are classified as endogenous opioids, meaning they are naturally produced within the body and interact with the same receptors targeted by opioid drugs. Structurally, they are pentapeptides, which are short chains composed of five amino acids. They are derived from a larger precursor protein called proenkephalin, which is cleaved by enzymes to yield the active forms. There are two primary types: Met-enkephalin and Leu-enkephalin, distinguished only by their final amino acid. This subtle chemical difference influences the specific receptors each molecule binds to within the nervous system.
How Enkephalins Signal in the Nervous System
Enkephalins function as chemical messengers (neurotransmitters and neuromodulators), transmitting or altering signals between nerve cells throughout the central and peripheral nervous systems. Their mechanism of action involves binding to specialized proteins on the surface of neurons known as opioid receptors, which are widely distributed across the body. Enkephalins are considered the primary natural ligands for the delta-opioid receptor (DOR), showing the highest affinity for this type. Binding to DOR, and to a lesser extent the mu- (MOR) and kappa-opioid receptors (KOR), triggers a cascade of events that inhibits neuronal activity. This interaction suppresses the release of neurotransmitters, such as Substance P and glutamate, that communicate pain signals across the synapse, thereby reducing the intensity of the pain signal that reaches the brain.
Primary Roles in Pain and Stress Response
Pain and Stress Regulation
The most recognized function of enkephalins is their role in natural pain relief, or analgesia, a process that occurs in response to physical discomfort or injury. They are released during events like intense physical activity, trauma, or periods of high stress, forming part of the body’s immediate coping mechanism. This release dampens the perception of pain, allowing the organism to continue functioning or escape a threatening situation. Enkephalins are also involved in regulating emotional states and the body’s reaction to stress. They modulate the hypothalamic-pituitary-adrenal (HPA) axis by inhibiting the secretion of corticotropin-releasing factor, which helps prevent the over-activation of the stress response and influences mood and anxiety levels.
Reward Circuitry
The enkephalin system also contributes to the brain’s reward circuitry, a function separate from analgesia. They are highly expressed in reward-related areas, such as the ventral tegmental area and the nucleus accumbens, where their signaling enhances feelings of well-being. By modulating neurotransmitters like dopamine in these pathways, enkephalins reinforce behaviors beneficial for survival, such as feeding and social interaction.
Therapeutic Targeting of Enkephalin Pathways
Enkephalin Degradation
A limitation of the natural enkephalin system is the short duration of the molecules’ action after release. Enkephalins are rapidly metabolized and inactivated by enkephalinases, enzymes that cleave the pentapeptide into inactive fragments. This quick degradation ensures the body’s response is tightly regulated and temporary.
Inhibitor Therapy
The therapeutic strategy involves using enkephalinase inhibitors, compounds designed to block these degrading enzymes. By inhibiting enzymes like neutral endopeptidase (NEP) and aminopeptidase N (APN), these drugs prevent the breakdown of naturally released enkephalins. This inhibition prolongs enkephalin activity at receptor sites, enhancing the body’s intrinsic pain-relieving effects. This approach holds promise for new pain management options because it leverages the body’s own system while minimizing risks associated with traditional opioid medications. Inhibitors are being studied as a non-addictive alternative for chronic pain, producing analgesia indirectly without the full spectrum of side effects, such as dependence and respiratory depression, often seen with exogenous opioids.