What exactly are opioids, and why are they important?
Opioids are chemicals that are similarly structured to naturally-produced opiates, which we call endogenous opioids. Have you heard of serotonin or oxytocin? Opioids are similar to these chemicals in that they can attach to specialized proteins called mu opioid receptors and G protein-coupled receptors on neurons, and it catalyzes the mesolimbic (midbrain) reward system governed by the basal ganglia.
Dopamine is released from the nucleus accumbens (NAc), which trigger feelings of pleasure as if you had just been rewarded. While opioids were once used to treat extreme pain in patients, misuse of opioids have led to an estimated over 841,000 overdose deaths in the United States since 1999 (CDC, 2020). During the release of dopamine, other parts of the brain continue to gather information about your surroundings to associate the good feelings you had, creating conditioned associations, memories of the euphoria, and thus trapping those who use opioids on a road to addiction and loss of control.
First, we need to understand the parts of the brain that process the feelings of euphoria, pleasure, reward, motivation, and conversely, disgust and avoidance: the midbrain, specifically the basal ganglia.
Dopamine is produced by the substantia nigra, ventral tegmental area, and hypothalamus (Juárez Olguín et al., 2016). The substantia nigra is a nucleus part of the basal ganglia (responsible for motor learning, habits, executive functions, and emotions), and it is located in the “midbrain posterior to the crus cerebri fibers of the cerebral peduncle,” meaning it is in front of the crus cerebri fibers of the cerebral peduncle, the two stalks that connect the brainstem to the cerebrum responsible for movement and communication with the spinal cord. The ventral tegmental area, or VTA, is also part of the midbrain next to the SN, and it is often confused with it and the surrounding nuclei. This is because the VTA is also important in reward cognition, which consists of the motivational salience process of recognizing rewards and motivating behaviors, associative learning, and positively-valenced emotions.
The primary motor cortex is located on the top, or dorsal area, of the brain in the frontal lobe. It works with the premotor cortex and is defined as the group of neurons called the Betz cells which are long cells that send signals to the spinal cord. The primary function of the prefrontal motor cortex is of course, controlling the body, but this does not mean that the largest parts of your body will have the most amount of surface area covered in the brain. On the contrary, the representation of different body parts and the primary motor cortex has been described by the Latin phrase homunculus, or “little person,” because the arms and hands actually use up more surface area in the brain. It is known that the primary motor cortex receives sensory information from the thalamus, a part of the grey matter in the middle of the brain that transmits visual information, taste, touch, and balance (although not smell). However, there is actually not that much research on how a neuron from a Betz cell from the primary motor cortex may actually send a signal all the way to a muscle in the body from every single other neuron it communicates with all the way to the spinal cord and motor neurons.
The primary somatosensory cortex (S1) is responsible for representing and processing the environment around us, so it is crucial in movement and spatial recognition (Borich et al., 2015). Researchers have used neuroimaging and neurostimulation experiments to show how lesions in this area can cause agraphesthesia (termed “disoriented cutaneous kinesthesia/proprioception” or the inability to feel your skin), astereognosia (the inability to identify what you are touching), and other disorders relating to the skin and touch.
The caudate nucleus is composed of two parts that are part of the thalamus in the middle of the brain, and it helps in communicating with the basal ganglia, responsible for motor control, executive functions, and habits. The putamen also helps in communicating input from the cerebral cortex to the basal ganglia.
Different from the caudate nucleus, however, the putamen sends more afferents (or sensory information) to the internal globus pallidus. The globus pallidus is responsible for voluntary movement, and pallidotomy is characterized as damage in the globus pallidus, and it can induce involuntary muscle tremors. Together, the caudate nucleus and the putamen form the dorsal striatum of the brain, which is the main part of the brain that sends information to the basal ganglia.
The ventral striatum is another part of the basal ganglia, which contains the nucleus accumbens and the olfactory tubercle. The nucleus accumbens is responsible for processing different neurotransmitters, such as dopamine (from rewarding stimuli, amphetamines, cocaine, nicotine, and morphine), phenethylamine, tyramine, GABA, glutamate, and serotonin.
The amygdala is generally responsible for creating memories and storing them with emotions. During fear conditioning, the amygdala is activated and is connected to signalling with the central nucleus, a crucial part of the amygdala responsible for reacting to pain and the “fight, flight, or freeze response” we commonly hear about. Different from the striatum, the amygdala has many glutamatergic neurons instead of GABAergic neurons.
It was generally accepted that opioids, both endogenous and exogenous, were processed similarly, making treatments for opioid addiction difficult. However, recent research from the University of California, San Francisco has shown that addictive opioids such as morphine may be different from endogenous opioids like endorphins (Stoeber et al., 2018). While endogenous opioids seem to be concentrated near the endosomes inside the cells that produce them, it seems that exogenous opioid drugs are taken care of more in the Golgi apparatus, and they are processed much more quickly. As a result, some researchers theorize that the unwanted side effects of extreme euphoria (instead of controlled pain relief) may be due to this unique characteristic of current opioid drugs. More research is needed, then, to see whether it may be possible to produce an opioid clinical pain reliever that cannot be easily abused and misused.
Citations
Borich, M. R., Brodie, S. M., Gray, W. A., Ionta, S., & Boyd, L. A. (2015). Understanding the role of the primary somatosensory cortex: Opportunities for rehabilitation. Neuropsychologia, 79(Pt B), 246–255. https://doi.org/10.1016/j.neuropsychologia.2015.07.007
Center for Disease Control and Prevention. National Center for Health Statistics; 2020. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA. Available at http://wonder.cdc.gov.
Juárez Olguín, H., Calderón Guzmán, D., Hernández García, E., & Barragán Mejía, G. (2016). The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxidative medicine and cellular longevity, 2016, 9730467. https://doi.org/10.1155/2016/9730467
Kosten, T. R., & George, T. P. (2002). The neurobiology of opioid dependence: implications for treatment. Science & practice perspectives, 1(1), 13–20. https://doi.org/10.1151/spp021113
Stoeber M, Jullié D, Lobingier BT, Laeremans T, Steyaert J, Schiller PW, Manglik A, von Zastrow M. A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action. Neuron. 2018 May 5. pii: S0896-6273(18)30329-5. doi: 10.1016/j.neuron.2018.04.021. [Epub ahead of print]. PMID: 29754753.
