How endorphins produce pain relief and reward effects in peripheral nerves and the brain. Effects of endorphin on substance P, GABA and dopamine release. Physical exercise and endorphins.

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Endorphins, for endogenous morphine, are opioids that occur naturally in human body. They are so named because they bind to the same opioid receptors in the nervous system as morphine, and produce morphine-like effects such as pain relief and euphoria.
There are 3 endorphins: alpha-, beta- and gamma-endorphins. All three are short peptides derived from the common precursor protein proopiomelanocortin, POMC. POMC is synthesized in pituitary gland, hypothalamus, medulla and some other tissues outside the brain. Beta-endorphin is most studied and represents the bulk of knowledge we have about endorphins in general.
Endorphins are released in response to a number of stimuli, with the major stimulus being pain. They exert their effects by binding to opioid receptors in both central and peripheral nervous systems.
In peripheral nerves, binding of endorphins, specifically beta-endorphin, to opioid receptors, in particular mu-receptor, prevents the release of substance P, a key factor in transmission of pain signals.
In the brain, the same binding between beta-endorphin and its receptor leads to increased dopamine release. Dopamine is the neurotransmitter that underlies the brain reward pathway. Engaging in enjoyable activities causes dopamine release from dopamine-producing neurons into the synaptic space, where it binds to and stimulates dopamine-receptors on the receiving neuron. This stimulation is believed to produce the pleasurable feelings or rewarding effect. Normally, GABA, another neurotransmitter, inhibits dopamine release in the nucleus accumbens. By binding to receptors on GABA inhibitory neurons, endorphins reduce GABA’s activity, ultimately increase dopamine release and induce pleasurable feelings. Dopamine release in response to pain signals may explain why pain can sometimes feel “good”.
Endorphins are also produced in response to pleasurable activities, meditation, laughter, and vigorous exercise; and these factors have been shown to increase one’s tolerance to pain. Endorphins are thought to contribute to the “runner’s high” sensation, a euphoric state some people experience after intense exercise. They may also underlie “exercise addiction”, in which the brain is desensitized due to repeated and excessive exposures to endorphins; and people keep increasing the amount of exercise in order to achieve the same desired sensation

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