Your nervous system is your body's information network. The brain and spinal cord do the processing and decision-making, the nerves branching out from them carry the signals to and from every muscle, organ, and patch of skin. The brain runs on the same building block as every nerve in your toes: the neuron, a specialised cell whose entire job is transmitting information.
Neurons
A neuron is a specific type of cell that the brain and nervous system are made of for transmitting information.
A neuron has three main parts:
- Cell body (soma): contains the nucleus, DNA, and the cell's machinery (same as any other cell)
- Dendrites: branch-like extensions that receive incoming signals from other neurons
- Axon: a long projection that sends signals out to other neurons or muscles. Some axons are very short, others can be over a metre long running from your spinal cord to your foot
Neurons talk to each other through a combination of electrical and chemical signals.
- An electrical signal travels down the axon
- At the end of the axon it triggers the release of neurotransmitters (chemical messengers) into a tiny gap called the synapse
- The neurotransmitters cross the synapse and bind to receptors on the next neuron's dendrites
- This triggers a new electrical signal in that neuron
This is happening billions of times per second throughout your brain and nervous system.
You're born with roughly 86 billion neurons and for the most part you keep them for life. Neurons don't replace themselves, keeping them alive and healthy is entirely dependent on survival signals, which is what neurotrophins provide.
They form incredibly specific networks and connections & they are energy hungry, the brain uses about 20% of your total energy.
For a long time scientists believed zero new neurons were ever produced after birth. This turned out to be partially wrong. The hippocampus (the memory region) continues producing new neurons throughout life in a process called neurogenesis.
Neurotransmitters
Neurotransmitters are the chemical messengers neurons use to communicate across the synapse. The electrical signal travels down the axon, but it can't jump the gap between neurons, so at the synapse it gets converted into a chemical signal. The neurotransmitter crosses the gap, binds to a receptor on the next neuron, and either excites or inhibits it.
Every neurotransmitter does one of two things:
- Excitatory: makes the receiving neuron more likely to fire. Increases the electrical signal
- Inhibitory: makes the receiving neuron less likely to fire. Quietens it down
The balance between excitation and inhibition across billions of synapses simultaneously is what produces every thought, feeling, sensation, and movement.
Main ones worth knowing:
- Glutamate: the primary excitatory neurotransmitter. The main "go" signal throughout the brain
- GABA: the primary inhibitory neurotransmitter. The main "stop" signal. Alcohol works partly by enhancing GABA — which is why everything slows down
- Dopamine: reward, motivation, movement. Not primarily excitatory or inhibitory — it modulates how strongly other signals are weighted
- Serotonin: mood, sleep, appetite regulation. Also modulatory rather than simply on/off
- Noradrenaline (norepinephrine): alertness, attention, fight or flight response
- Acetylcholine: muscle activation, memory formation, attention
Every one of these works by binding to a receptor on the receiving
neuron, which opens a channel for a specific ion. What the
neurotransmitter does to the neuron depends entirely on which ion
flows in or out.
neuron, which opens a channel for a specific ion. What the
neurotransmitter does to the neuron depends entirely on which ion
flows in or out.
- Sodium (Na+): flows in. Makes the inside of the cell positive,
the neuron fires. Job: firing.
- Potassium (K+): flows out. Makes the inside more negative, the
neuron is harder to fire. Job: quieting.
- Chloride (Cl-): flows in. Negative charge in, also makes the
inside more negative. Job: quieting. This is what GABA does.
- Calcium (Ca2+): flows in. Not just for electrical charge, calcium
is also a powerful signal inside the cell. Triggers vesicle release,
gene expression changes, learning, and at excess levels, cell death. Job: signalling and triggering downstream events.
The electrical signal itself is called an action potential. At
rest, the inside of a neuron is negatively charged. When the neuron
gets excited enough, sodium channels open, sodium rushes in, the
inside flips positive, and the signal fires down the axon. Then
potassium channels open, potassium flows out, and the neuron resets
to its negative resting state, ready to fire again.
rest, the inside of a neuron is negatively charged. When the neuron
gets excited enough, sodium channels open, sodium rushes in, the
inside flips positive, and the signal fires down the axon. Then
potassium channels open, potassium flows out, and the neuron resets
to its negative resting state, ready to fire again.
The whole point of inhibition (GABA, glycine, opioids) is to keep
the inside extra negative so it's harder to flip positive. That's
how quieting works at the cellular level.
the inside extra negative so it's harder to flip positive. That's
how quieting works at the cellular level.
Glutamate
Glutamate is your brain's "go" signal. Every time a neuron needs to tell the next one to fire, glutamate is what carries the message. Glutamate opens sodium channels (firing) and calcium channels (learning and, in excess, damage). It's behind almost all the active, productive stuff your brain does: learning, focus, memory formation, and the literal physical strengthening of neural connections every time you practice something or pick up a new skill. Lifting heavier each week, getting better at chess, remembering what you read this morning, that's glutamate signalling building stronger synaptic pathways.
Glutamate is also the primary neurotransmitter in pain signalling. Pain signals travel through neurons using glutamate as the excitatory signal that keeps the pain message firing and moving up to the brain. The body's natural painkillers (endorphins, enkephalins) work partly by suppressing glutamate release at the synapse, reducing the excitatory signal that carries pain.
When neurons release excessive glutamate, it overstimulates receiving neurons to the point of damage or death, a process called excitotoxicity.
Chronic over-excitation, whether from stress, lack of sleep, or stacking stimulants, pushes the system toward this same edge. You feel wired, anxious, can't focus, can't sleep. That's the brain trying to dampen excess glutamate signalling.
When neurons get over-excited (head injury, stroke), the calcium influx through NMDA receptors goes into overdrive and damages or kills the cell.
You want glutamate signalling strong and responsive when you're working, training, learning, but you don't want it stuck on at night or when you're trying to recover
Pain signals travel through neurons using glutamate as the primary excitatory signal. The body's natural painkillers work by binding to opioid receptors on nerve cells, which suppresses glutamate release at the synapse and simultaneously opens potassium channels.
Opioid drugs (morphine, fentanyl, codeine) mimic endorphins by binding directly to the same opioid receptors, producing the same inhibitory effect but at much higher intensity and for longer duration than your body's natural version.
NSAIDs (ibuprofen, aspirin) work through a completely different mechanism. They block enzymes called COX-1 and COX-2 which produce prostaglandins, signalling molecules that sensitise pain receptors and cause inflammation. Less prostaglandins = pain receptors are less sensitive = less pain perceived.
Paracetamol is still not fully understood. It appears to work centrally in the brain rather than at the site of pain, possibly through the endocannabinoid system and serotonin pathways. Not opioid receptor based.
Local anaesthetics (lidocaine, dentist injections) block sodium channels in nerve cell membranes entirely, the electrical signal literally cannot travel. The nerve is temporarily unable to fire at all.
GABA
GABA (gamma-aminobutyric acid) is the brain's primary inhibitory neurotransmitter, the counterbalance to glutamate. Where glutamate says "fire," GABA says "don't fire." It works by opening chloride channels on the receiving neuron, which makes the inside of the cell more negative (hyperpolarised) and therefore harder to excite. The balance between glutamate (excitation) and GABA (inhibition) across billions of synapses is what keeps neural activity in a functional range.
GABA is the brain's main mechanism for calming neural circuits down. It's critical for sleep (GABA activity increases during the transition to sleep), anxiety regulation (adequate GABA keeps the amygdala and stress circuits from becoming hyperactive), muscle relaxation, and preventing seizures (seizures are essentially runaway excitation without enough GABA to stop it).
Anxiety at the neurological level is essentially too much excitation relative to inhibition in certain brain circuits, particularly the amygdala and prefrontal cortex. GABA is the primary brake on this. When GABA signalling is inadequate, the amygdala becomes hyperreactive, firing too easily in response to perceived threats, and the prefrontal cortex can't regulate it effectively. Most anti-anxiety drugs work by enhancing GABA: benzodiazepines (Valium, Xanax) bind to GABA receptors and amplify the inhibitory effect, making each GABA molecule more powerful. Alcohol also enhances GABA signalling, which is why it initially calms anxiety but causes rebound anxiety when it wears off, the brain compensates for the enhanced inhibition by upregulating excitation, and when the alcohol leaves you're left with more excitation than baseline.
Two different types of GABA receptor that do different jobs.
- GABA-A: fast, opens chloride channels, immediate quieting, what alcohol and Xanax hit.
- GABA-B: slow, opens potassium channels through a signalling cascade, sustained dampening, what baclofen and GHB hit.
Both quiet neurons but through different mechanisms and on different timescales.
Dopamine
Dopamine is the neurotransmitter behind motivation, reward, drive, and goal-directed behaviour. It's often described as the "pleasure chemical" but that's misleading. Dopamine is more accurately the "wanting" chemical. It drives you to pursue things, not just enjoy them. The difference matters: dopamine spikes in anticipation of a reward, not just on receipt of it. It's what makes you get up and go after something.
Dopamine operates through several distinct pathways in the brain, each doing different things:
The mesolimbic pathway (from the ventral tegmental area to the nucleus accumbens) is the reward and motivation circuit. This is the pathway that makes you want to pursue goals, take action, and feel rewarded when you achieve something. It's also the pathway hijacked by addictive substances and behaviours, drugs, social media, gambling, and pornography all produce dopamine spikes in this circuit that the brain wasn't designed to handle at that frequency or intensity.
The mesocortical pathway (from the ventral tegmental area to the prefrontal cortex) supports executive function, working memory, attention, and decision-making. Low dopamine in this pathway manifests as brain fog, poor concentration, and difficulty planning or following through.
The nigrostriatal pathway (from the substantia nigra to the striatum) controls voluntary movement. The death of dopamine-producing neurons in this pathway is what causes Parkinson's disease, which is why Parkinson's symptoms are primarily movement-related (tremor, rigidity, slowness).
Testosterone increases dopamine synthesis and release in the mesolimbic pathway, which is one of the direct mechanisms by which testosterone influences motivation and drive. Low testosterone reduces dopamine output in this circuit, which is why low T often presents as apathy, lack of motivation, and reduced ambition before it presents as overtly depressive symptoms. Prolactin, covered on the hormonal system page, has an inverse relationship with dopamine, high prolactin suppresses dopamine and vice versa.
Serotonin
Serotonin is the neurotransmitter most associated with mood stability, emotional resilience, and baseline wellbeing. Where dopamine drives the peaks (motivation, reward, excitement), serotonin sets the floor (how stable, calm, and emotionally resilient you are between those peaks). It's produced by neurons in the raphe nuclei in the brainstem, which project throughout the brain.
Serotonin doesn't make you "happy" in the way dopamine makes you feel rewarded. It makes you stable. Adequate serotonin means your mood has a solid baseline, negative events don't pull you into spirals, you recover from setbacks, and you feel generally okay without needing external stimulation. Low serotonin means the floor drops, you're more vulnerable to anxiety, irritability, rumination, and being pulled into low mood states by normal life stressors you'd otherwise handle fine.
Serotonin modulates how the amygdala responds to negative stimuli. When serotonin signalling is adequate, the amygdala's response to perceived threats is proportional, you react appropriately and recover. When serotonin is low, the amygdala becomes hyperreactive, you overreact to negative events, feel more anxious, and have difficulty letting things go.
Serotonin also regulates impulse control and aggression (low serotonin is associated with increased impulsivity and reactive aggression), sleep-wake cycles (serotonin is a precursor to melatonin, the sleep hormone produced by the pineal gland), appetite, and pain perception (low serotonin is associated with increased pain sensitivity, which is one reason depression and chronic pain so frequently co-occur).
Serotonin also acts as a brake on dopamine. Serotonin neurons project directly into the dopamine reward circuit, and when serotonin signalling there is high, dopamine release goes down.
This is why SSRIs make so many people feel "flat." Less anxious, less sad, but also less motivated, less excited, less interested in things they used to enjoy. That's not just a side effect, it's the same mechanism doing its job, more serotonin = less dopamine drive in the reward circuit. The emotional blunting and sexual dysfunction people report on SSRIs come from the same place.
It's also one reason elevated oestrogen can reduce libido. Oestrogen boosts serotonin signalling, which dampens dopamine-driven desire in the same circuit.
Testosterone modulates the serotonin system by influencing serotonin transporter (SERT) expression and serotonin receptor density. SERT is the protein that reabsorbs serotonin from the synapse back into the presynaptic neuron, the same transporter that SSRIs block. When testosterone is adequate, serotonin signalling is maintained efficiently. When testosterone drops, serotonin signalling becomes less efficient, which is one of the direct mechanisms by which low testosterone causes depression, anxiety, and irritability.
Noradrenaline (norepinephrine)
Noradrenaline is the brain's alertness and vigilance neurotransmitter. It's produced by neurons in the locus coeruleus in the brainstem, which project widely throughout the brain. Noradrenaline sharpens attention, increases arousal, enhances focus, and prepares the brain for action. It's the neurological component of the fight-or-flight response, the brain's version of what the adrenal medulla releases as a hormone (adrenaline/noradrenaline) into the bloodstream.
At normal levels, noradrenaline supports focused attention, alertness, and the ability to respond to important stimuli while filtering out irrelevant ones. At elevated levels (chronic stress, anxiety disorders), it creates hypervigilance, restlessness, difficulty relaxing, and an overactive startle response. At very low levels, it manifests as lethargy, poor concentration, and lack of alertness.
Noradrenaline is synthesised from dopamine, a direct enzymatic conversion by the enzyme dopamine beta-hydroxylase. This means dopamine is literally the precursor to noradrenaline, and anything that affects dopamine production upstream (including testosterone) can indirectly influence noradrenaline availability. Copper is required as a cofactor for this conversion, which connects to the copper discussion on the zinc compound page.
Many stimulant medications (Adderall, Ritalin) and antidepressants (SNRIs like venlafaxine, duloxetine) work partly by increasing noradrenaline availability at the synapse.
Acetylcholine
Acetylcholine was the first neurotransmitter ever discovered and has two major roles: it's the neurotransmitter that activates voluntary muscles (every time you contract a muscle, acetylcholine carries the signal from the motor neuron to the muscle fibre), and in the brain it's critical for memory formation, attention, and learning.
Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. The enzyme that catalyzes this is called choline acetyltransferase (ChAT). It picks up an acetyl group from acetyl-CoA and sticks it onto choline.
The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role in arousal, attention, memory and motivation.
Acetylcholine is produced primarily by neurons in the basal forebrain. Acetylcholine in the cortex supports sustained attention and the ability to focus on relevant information. Acetylcholine in the hippocampus is essential for encoding new memories, strengthening synaptic connections during learning.
At the neuromuscular junction (where motor neurons meet muscle fibres), acetylcholine is released from the nerve ending, crosses the synaptic cleft, and binds to nicotinic receptors on the muscle fibre, triggering contraction. This is why nerve agents and certain toxins that block acetylcholine signalling cause paralysis, the muscles can't receive the contraction signal. Conversely, myasthenia gravis (an autoimmune condition where the body attacks its own acetylcholine receptors) causes progressive muscle weakness because the signal can't get through.
Nicotine gets its name from the nicotinic acetylcholine receptor, it mimics acetylcholine by binding to the same receptors, which is why nicotine initially enhances focus, attention, and alertness. It's also why nicotine withdrawal causes cognitive fog and difficulty concentrating, the brain has downregulated its own acetylcholine receptor sensitivity in response to the external stimulation.
Neurotrophins
Neurotrophins are a broader family of proteins. They all do similar things: promote nerve cell survival, growth, and function. The brain and nervous system are continuously losing neurons with age. Neurotrophins are what keep existing neurons alive and functional.
The main ones are:
- NGF — primarily supports sensory nerves and parts of the brain involved in memory and learning
- BDNF (Brain-Derived Neurotrophic Factor) — the most well studied, supports neurons throughout the brain, critical for memory formation and mood regulation
Neurotrophin levels decline with age and this decline maps closely onto the cognitive and neurological changes we associate with aging.
Brain-Derived Neurotrophic Factor (BDNF)
BDNF (Brain-Derived Neurotrophic Factor) is the brain's master growth and plasticity signal. It does for neurons what testosterone does for muscle, it's what tells existing neurons to grow new branches and form new connections, and it's what allows the hippocampus to produce new neurons throughout life (the rare exception to the "no new neurons" rule).
BDNF is what makes learning work. Every time you practice something, study, train a skill, or form a memory, BDNF is what physically strengthens the synapses involved. No BDNF, no learning, no memory consolidation.
Depressed brains show lower BDNF. SSRIs, ketamine, and even ECT all converge on raising BDNF. This is why SSRIs take 4-6 weeks to work despite raising serotonin within hours, you're waiting for BDNF to rebuild synaptic infrastructure. Ketamine works in hours because it triggers a rapid BDNF spike through a different mechanism.
Other things that raise BDNF :
- Aerobic exercise (the strongest lever)
- Quality sleep, particularly deep sleep
- Caloric restriction and fasting
- Cold exposure
- Learning new skills, especially complex motor skills
- Sunlight and adequate vitamin D
- Omega-3 intake (DHA specifically)
- Coffee/caffeine (modest effect)
Things that lower BDNF:
- Chronic stress and elevated cortisol (this is a major one, chronic stress literally shrinks the hippocampus partly through BDNF suppression)
- Poor sleep
- Chronic alcohol use
- Sedentary behaviour
- Inflammation and high refined carb intake
- Social isolation
Nerve Growth Factor (NGF)
NGF and BDNF do similar work but on different neurons. BDNF acts broadly across the brain. NGF acts on a narrower set: the cholinergic neurons of the basal forebrain (the acetylcholine producers that feed attention and memory signals to the cortex and hippocampus), the sensory nerves carrying pain and touch, and the sympathetic nerves of the fight-or-flight system.
Some compounds directly upregulate NGF, the most well-known being 
Lion's Mane Mushroom
Our brain
The brain has three main parts: the cerebrum, the cerebellum, and the brainstem.
The cerebrum is the big wrinkled part, the conscious processing centre. Its outer layer (the cortex) is split into four lobes: the frontal lobe runs decision-making, planning, personality, and impulse control.
The parietal lobe processes touch, temperature, and pressure. The temporal lobe handles hearing and contains the hippocampus and amygdala deep inside.
The occipital lobe processes vision.
Two specific strips of cortex sit either side of the central sulcus, the groove that separates the frontal and parietal lobes. In front of it is the primary motor cortex, which sends movement commands to your muscles. Just behind it is the primary somatosensory cortex, which receives touch and sensation back from the body. Different parts of each strip correspond to different body parts.
The cerebellum sits at the back, below the cerebrum. It's about 10% of the brain by volume but holds more than 50% of its neurons. It runs balance, coordination, and fine motor skills.
The brainstem connects the brain to the spinal cord. Every signal between the two passes through it, and it runs the autonomic stuff you don't think about: breathing, heart rate, blood pressure, digestion, sleep-wake cycles.
Thalamus
Two thalami sit just above the brainstem, one in each hemisphere, near the centre of the brain. The thalamus is the gateway to the cortex: nearly every sensory signal entering your brain (every sight, sound, touch, taste, the only exception is smell) passes through the thalamus first before being routed to the cortex for processing. It contains roughly 50 distinct nuclei, each handling a different type of information.
What this means practically: the thalamus is also one of the structures that "switches off" the outside world when you sleep, gating sensory input so your cortex can do its overnight maintenance. Drugs that disrupt thalamic gating (alcohol, ketamine, general anaesthetics) all produce some version of dissociation or unconsciousness because they're interrupting this filtering function.
Hippocampus
Two hippocampi sit deep within the temporal lobes, one in each hemisphere.
The hippocampus is where new memories are encoded, particularly declarative memories (facts and events you can consciously recall) and spatial memory (knowing where you are and how to navigate). It's the structure London taxi drivers physically grow through years of memorising the city, and the structure that shrinks in chronic stress, depression, and Alzheimer's.
It's one of the only brain regions that grows new neurons throughout life. This process, neurogenesis, happens in the dentate gyrus of the hippocampus and is heavily dependent on BDNF. Hippocampal neurons are unusually sensitive to cortisol, glutamate excitotoxicity, and inflammation. Chronic stress measurably shrinks the hippocampus on MRI, and why people with PTSD, major depression, or long-term untreated anxiety tend to have smaller hippocampi than controls.
The blackouts heavy drinkers experience are failures of hippocampal encoding. The hippocampus is unusually sensitive to alcohol's NMDA-blocking effect, so above a certain blood alcohol level it simply stops writing new memories.
Memory issues are usually the first sign something is off. Whether it's poor sleep, chronic stress, early hormonal decline, or actual neurodegeneration, the hippocampus is typically the first structure to show wear.
Amygdala
The amygdala is a cluster of nuclei in the temporal lobe, almond-shaped, two of them, one per hemisphere. Historically described as the brain's fear centre, but that framing is too narrow. The amygdala processes emotional salience in general (positive and negative), tags memories with emotional weight, and decides what your brain pays attention to.
When the amygdala detects something it reads as a threat through sensory input, it fires a signal to the hypothalamus, which triggers the HPA axis (cortisol response) and the sympathetic nervous system (adrenaline, heart rate, ready-to-move state). This happens faster than conscious thought. By the time you "decide" you're scared, the amygdala has already started the cascade.
Anxiety, at the neurological level, is largely an amygdala that's too reactive. A well-regulated amygdala fires appropriately and resets. A hyperreactive one fires at things that aren't real threats (a notification, a slightly tense text, a stranger's expression) and stays elevated. Most anti-anxiety drugs work by either dampening the amygdala directly (benzodiazepines, alcohol) or by improving the prefrontal cortex's ability to regulate it (SSRIs over time, therapy). Chronic stress makes the amygdala bigger and more reactive.
When the amygdala fires during an experience, it tells the hippocampus to encode that memory more strongly. This is why you remember exactly where you were during a major event but can't recall what you had for lunch on a regular Tuesday. It's also why traumatic memories embed so deeply, the amygdala's involvement essentially burns them in.
Hypothalamus
Located just below the thalamus, at the base of the brain, the hypothalamus is about the size of an almond but runs more of your body than any other structure that small has any right to. It sits directly above the pituitary gland and is connected to it by a stalk called the infundibulum.
The hypothalamus is your body's homeostasis controller. It constantly monitors core temperature, hydration, blood sugar, hormone levels, and stress signals, and it triggers whatever response is needed to keep everything in range:
- Thirst and fluid balance
- Hunger and feeding
- Body temperature
- Stress response (via the HPA axis, see below)
- Reproductive behaviour and sex hormone release (via the HPG axis)
- Circadian rhythm and the sleep-wake cycle
- Aggression and emotional regulation alongside the amygdala
It does this through three main regions:
The preoptic area (front) handles temperature regulation, fever, fluid balance, circadian rhythm, and sexual behaviour.
The tuberal hypothalamus (middle) connects to the pituitary and runs hunger, sexual function, and most of the endocrine signalling. It contains the paraventricular nucleus (PVN), which releases CRH to start the HPA axis cascade.
The posterior hypothalamus runs wakefulness, arousal, stress responses, and blood pressure.
Practically, the hypothalamus is the structure standing between your brain and almost every hormone in your body. Low testosterone, irregular menstrual cycles, disrupted sleep, weight changes, temperature dysregulation, chronic stress symptoms all run through here. It's also why chronic under-eating, over-training, or sleep deprivation cascade into hormonal problems so fast, the hypothalamus reads them as emergencies and starts shutting down "optional" systems like reproduction to conserve resources.
The hypothalamus is also the starting point for the body's three major hormone cascades, the HPA axis (stress, cortisol), the HPT axis (thyroid), and the HPG axis (sex hormones). Each one runs from the hypothalamus to the pituitary to a target gland.
The HPA Axis
The HPA axis includes a group of hormone-secreting glands from the nervous and endocrine systems, with the primary function of regulating the body's stress response. It functions as a three-level alarm system that activates whenever you face physical or psychological stress.
The hypothalamus controls the release of hormones from the pituitary gland. When we experience something stressful, the hypothalamus releases a hormone called corticotropin-releasing hormone (CRH). CRH signals the pituitary gland to secrete adrenocorticotropic hormone (ACTH) into the bloodstream, which travels to the adrenal glands. This prompts the release of cortisol and other hormones like DHEA-S. Cortisol causes a number of changes that help the body deal with stress, including increasing blood sugar, suppressing non-essential functions, and increasing alertness.
When cortisol levels in the blood get high enough, this is sensed by receptors in areas of the brain like the hypothalamus and hippocampus, which leads to the shutting off of the stress response through a negative feedback mechanism.
POMC (Proopiomelanocortin)
POMC is one of the body's most economical proteins. It's a single precursor that gets cleaved into completely different hormones depending on which tissue does the processing, and through it the stress response, appetite, skin pigmentation, sexual arousal, and pain relief are all biochemically linked.
It's produced mainly in the pituitary and in certain hypothalamic neurons. Skin cells also produce it locally in response to UV, which is part of why you tan. The pituitary cleaves POMC mainly into ACTH (stress, cortisol). The hypothalamus cleaves it mainly into α-MSH (appetite, pigmentation, sexual arousal) and β-endorphin (pain relief, reward, the runner's high).
α-MSH
α-MSH binds to the five melanocortin receptors (MC1R through MC5R), each doing different things in different tissues:
- MC1R sits on melanocytes in the skin. α-MSH binding tells them to produce melanin, which is why you tan. People with certain MC1R variants (common in redheads) tan poorly and burn easily because their receptor barely responds to the signal
- MC2R is the ACTH receptor on the adrenal cortex, the one that triggers cortisol production. It only responds to ACTH, not α-MSH
- MC3R and MC4R sit in the hypothalamus and run appetite and energy balance. When α-MSH binds MC4R you feel full. Mutations in MC4R are the single most common genetic cause of severe early-onset obesity. MC4R also drives sexual arousal, which is the receptor PT-141 (Bremelanotide) hits to trigger dopamine release in the medial preoptic area
- MC5R is on sebaceous glands and other exocrine tissues. It regulates oil production in the skin and secretion from sweat and tear glands
α-MSH also has anti-inflammatory effects, suppressing TNF-α and IL-6 in immune cells.
β-endorphin
β-endorphin is the body's most potent natural painkiller. It binds μ-opioid receptors on nerve cells, suppressing glutamate release and opening potassium channels, both of which make neurons harder to fire. The result is pain dampening, euphoria, and reduced anxiety.
It's released during exercise (the runner's high), pain, stress, and sex. The fact that β-endorphin comes from the same precursor as ACTH explains why intense stress can initially feel numbing, the same signal that activates your stress response also releases your body's painkiller.
Opioid drugs (morphine, fentanyl, codeine) work by mimicking β-endorphin at these same receptors, but at much higher intensity and for longer duration than your body produces naturally. This is why opioid addiction is so physiologically powerful, the drugs hijack a system you already depend on for pain and reward.
ACTH
ACTH is the fragment of POMC that drives the stress response (covered in the HPA axis section above). The key point worth repeating: ACTH isn't sitting pre-made in the pituitary waiting to be released. It's manufactured in real time by cleaving POMC every time the stress response fires. This is why the whole POMC system is so interlinked, anything that affects POMC production or processing can simultaneously affect your stress response, pain tolerance, appetite, pigmentation, and sex drive.
Our Connective Tissue
Made with Bullet