We’ve all heard about endorphins- opioids our own body produces in response to pain and other stimuli. External opioids activate the same system, but over time can change how the body perceives and responds to pain, as well as pleasure. Opioid receptors are where all opioids, regardless of their source, have to interact. They are integral to any process that inhibits pain or enhances pleasure. Understanding how they work can help us find ways to manage pain on our own and ultimately find medications that improve the quality of life without harmful and addictive side effects.
Opioid receptors reside in nerve cells throughout the body and play a vital role in all its functions, not just analgesic effects. They are a vital aspect to reproduction, growth, weight, respiration, immunological responses as well as gastrointestinal function and pathophysiology. That’s why pharmacology that focuses on pain relief doesn’t just impact the pain, but the entire body as well.
Opioid receptors are found in the:
- Central nervous system
- Immune cells
- Pituitary gland
- Gastrointestinal tract
- Reproductive system
Endogenous opioids are those created within the body in response to a stimuli. Exogenous opioids, such as medications, are external to the body. Once activated they send a signal to the brain that controls feelings of reward and pain.
There are three types of opioid receptors
Mu- These are linked to mood, pain and reward. Once activated, these receptors encourage pain relief, elevated mood and respiratory changes. Most exogenous drugs and medications use this pathway.
Delta– It has been postulated that delta receptors may modulate chronic pain and Mu acute pain. They also appear to specifically affect a person’s mood, causing anxiety and depression when blocked in mice and mood elevation when activated.
Kappa– These receptors seem to affect not just mood, but reward responses as well, pain relief, increased urination and a profound sense of uneasiness and dissatisfaction with life or dysphoria. The opposite of euphoria.
and. . .
Nociceptin – Residing in the brain and spinal cord, it is considered to be a part of a subtype of opioid receptors. These deal with anxiety, depression and appetite. Activation stimulates food intake and regulates meal patterns. They also appear to have an impact on the development of tolerance to mu receptor agonists e.g. morphine, oxycodone.
Research suggests exogenous opioids affect receptor’s differently than endogenous ones. Opiates generated by our bodies activate receptors on both the surface and inside nerve cells at a specific location. Endogenous ones interact with and remain active within compartments known as endosomes and use these endosomes to sustain the signal within these cells. But exogenous opioids activate not only the local receptors but immediately seek out internal structures known as the Golgi apparatus and all their outposts, disseminating a signal throughout the body. Synthetic opioids reach their target in twenty seconds as opposed to over one minute for endogenous. And their effect lasts much longer. This widespread activation in the Golgi system and more sustainable reaction is believed to be the cause for their harmful and dangerous side effects.
How do opioids relieve pain?
It is theorized that the Mu-opioid receptors (MOR) act as a docking station that binds with naturally producing analgesics such as endorphins and enkephalins -nueropeptides that regulate nociception in the body (the sensory nervous system’s way to recognize painful stimuli and produce an appropriate defensive response). They are then released in a pulsatile fashion to specific parts of the body where they were activated, then metabolized quickly. This is unlike exogenous drugs like morphine, that flood the brain and body, sticking around for several hours.
What are endogenous opioids?
There are three types of endogenous opioids. Most of us know about endorphins, often alluded to as a “runner’s high”, because they are released after vigorous exercise. Enkephalins regulate the sensory nervous system’s response to pain. Dynorphins bind to the kappa receptors and affect weight control, temperature regulation, analgesia and mood by interacting with serotonin and dopamine levels.
They all act by binding to one of the four receptors defined above. But researchers have recently found a fifth opioid receptor that behaves differently. Known as “ACKR3” it is thought to fine tune brain levels of opioids. In the lab, opioids that bind to this receptor are dragged within the cell so they can’t bind with the other four receptors. They appear to act as a scavenger, looking for opioids and then hiding them so they can’t be activated, indirectly increasing pain signals. Stopping this action may be a great way to increase endogenous opioid levels and enhance our own pain killing abilities.
This is just one of the exciting new ideas being investigated to improve pain relief mechanisms without the devastating and harmful effects of what’s on the market today.
Until then, impacting our own endogenous opioid system, especially endorphins, is an important tool in pain management. I’ll discuss this in more depth next week.