Acute opioid neurobiology

Opioid drugs exhibit varying potency, efficacy, and pharmacokinetics at opioid receptors—mu (MORs), delta (DORs), and kappa (KORs)—an inhibitory class of G proteincoupled receptors (GPCRs). MORs and DORs mediate the analgesic and rewarding/addictive properties of opioids, whereas KORs have limited clinical analgesic properties due to undesirable effects such as dysphoria, anxiety, and hallucinations. We focus on MORs, the target of most opioid use disorder (OUD)-related research. MOR agonists lead to Gai/o activation, cAMP inhibition, receptor internalization, receptor phosphorylation by G protein receptor kinase (GRK), and recruitment of b-arrestin 2 (barr-2) and other downstream effectors including enzymes, ion channels, and small GTPase, thus regulating multiple signaling pathways including the mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK) phosphorylation cascade (Williams et al., 2013).

Recreational opioids such as heroin and prescription opioids (e.g., morphine, codeine, and oxycodone) are full MOR agonists. High-potency, synthetic opioids such as fentanyl are highly rewarding and exacerbate opioid overdose deaths. The actions of opioids and opioid-induced overdoses can be reversed by high-affinity MOR antagonists (e.g., naloxone) that displace opioids and inactivate MORs.

Chronic opioid neurobiology

With repeated opioid administration, tolerance occurs such that drug effects (analgesia, reward) are reduced, requiring higher doses to achieve similar effects as previous lower doses (Williams et al., 2013). Chronic use of opioids also leads to long-lasting alteration of other transmitter systems (e.g., dopamine [DA], glutamate, and GABA) contributing to altered synaptic plasticity. For example, chronic MOR activation increases surface expression of glutamatergic receptors (AMPA and NMDA receptor subunits), key regulators of synaptic function (Chartoff and Connery, 2014).

Neuronal organization and neural circuits

MORs are widely expressed in brain, including structures highly implicated in addiction. The mesolimbic reward pathway consists of the midbrain ventral tegmental area (VTA) and nucleus accumbens (NAc; ventral striatum). Direct activation of MORs in the NAc has positive hedonic properties. VTA DA neurons, which mediate reward, are regulated by GABAergic VTA interneurons and to a greater extent by GABA neurons originating from regions with abundant MOR expression including NAc, rostromedial tegmental nucleus (RMTg), and ventral pallidum (Galaj and Xi, 2021). Opioid activation of MORs reduces the release of GABA, an inhibitory neurotransmitter, thereby disinhibiting VTA DA neurons, resulting in excitation and increased DA levels in the NAc contributing to the acute rewarding effects of opioids (Johnson and North, 1992).

The dorsal striatum (caudate and putamen [Put]), which receives abundant midbrain DA input, plays a critical role in habitual behavior that emerges with opioid abuse. Similar to other drugs of abuse, chronic opioid use dysregulates glutamatergic processes relevant to synaptic plasticity (Kruyer et al., 2020). The prefrontal cortex (PFC), which includes the orbital frontal cortex (OFC), mediates decision-making, reward value, and goal-directed behavior, providing top-down glutamatergic regulation of subcortical regions as the NAc, dorsal striatum, and amygdala (Amyg). PFC and NAc activity is increased during drug craving in humans. Consistently, the PFC-NAc circuit is implicated in cue-induced reinstatement behavior in heroin self-administration animal models coinciding with increased NAc glutamate levels (Kruyer et al., 2020). The Amyg is also highly involved in emotional dysregulation of craving and negative affect often manifested during withdrawal.

Clinically, MOR agonists are important analgesics due to their ability to inhibit pain signals in the dorsal horn of the spinal cord. However, the increased use of opioids, as tolerance develops, and the use of highly potent drugs such as fentanyl increases overdose risk that can be fatal due to inhibition of the brainstem respiratory centers in the medulla and pons that have abundant MORs (Montandon and Horner, 2014).

Novel, emerging neurobiology

The dysregulation of the glutamatergic system seen with chronic opioid use is a growing area of research focus. Recent molecular evidence highlights epigenetic disturbances in the striatum of human heroin abusers linked to the nonreceptor tyrosine kinase Fyn that regulates glutamatergic signaling and cytoarchitectural organization (Egervari et al., 2020). FYN disturbances in striatal neurons in human heroin abusers are mimicked in rodents that self-administer heroin. Heroin increases both the active (phosphorylated) form of Fyn and phosphorylation (Tyr-18) of its downstream target Tau, highly implicated with neurocognitive decline. Studies of the human brain also emphasize epigenetic impairments of genes related to synaptic plasticity and glutamatergic neurotransmission that significantly correlate with certain epigenetic marks, e.g., H3K27 acetylation, which positively correlate with the years of heroin use (Egervari et al., 2017).

Conventional and novel theories for OUD treatment

Current standard treatments for OUD consists of substitution with another opioid with lower potency and longer half-life, such as methadone, to prevent periods of highs and withdrawal. Buprenorphine is also used clinically and is often formulated with naloxone (Suboxone) to block rewarding effects if inappropriately taken intravenously rather than orally.

Novel opioid ligands are evolving that attempt to leverage distinct intracellular signaling pathways that might differentially mediate MORs’ effects on reward, analgesia, and respiratory suppression. For example, G protein signaling and b-arrestin recruitment mediate analgesia and respiratory suppression, respectively (Schmid et al., 2017), whereas reward is driven by GRK-5 (Glück et al., 2014). This suggests that biased agonists, which stabilize MOR in a conformation that selectively activates a particular intracellular signaling cascade, might serve as potent analgesics without increasing addiction risk.

The need for non-opioid medications has also brought focus to the glutamatergic system. For example, a small molecule inhibitor of Fyn kinase reduces heroin-taking behavior in pre-clinical animal models (Egervari et al., 2020). Similarly, an inhibitor of acetylation epigenetic marks, associated with impaired glutamatergic signaling, decreases heroin self-administration (Egervari et al., 2017).

These and other emerging neurobiological findings relevant to OUD could offer new treatment strategies to significantly curb the opioid epidemic and help millions suffering from the disorder.

Acute Opioid Neurobiology

Opioid drugs interact with specific receptors in the body, known as mu (MORs), delta (DORs), and kappa (KORs) opioid receptors. These receptors are a type of G protein-coupled receptor (GPCR) that typically inhibit cell activity. MORs and DORs are responsible for the pain-relieving effects and the rewarding or addictive properties of opioids. KORs, however, offer limited pain relief in a clinical setting because they can cause unwanted effects such as feelings of distress, anxiety, and hallucinations. Most research on Opioid Use Disorder (OUD) focuses on MORs. When an opioid agonist activates a MOR, it triggers a series of cellular events. These include the activation of Gai/o proteins, which reduces cyclic AMP (cAMP) levels. The receptor then moves inside the cell, gets phosphorylated by G protein receptor kinase (GRK), and attracts beta-arrestin 2 (barr-2). These actions affect various signaling pathways, including the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, by influencing enzymes, ion channels, and small GTPase molecules.

Common recreational opioids like heroin and prescription opioids such as morphine, codeine, and oxycodone are full agonists of MORs. Highly potent synthetic opioids, like fentanyl, are particularly rewarding and significantly contribute to opioid overdose deaths. The effects of opioids and opioid-induced overdoses can be counteracted by high-affinity MOR antagonists, such as naloxone. These antagonists work by displacing opioids from the receptors and deactivating MORs.

Chronic Opioid Neurobiology

Repeated opioid use leads to the development of tolerance, where the effects of the drug, such as pain relief and reward, become reduced. Consequently, higher doses are needed to achieve the same effects that were once produced by lower doses. Long-term opioid use also causes lasting changes in other neurotransmitter systems, including dopamine (DA), glutamate, and GABA, which contribute to altered synaptic plasticity. For instance, continuous activation of MORs increases the presence of glutamatergic receptors (AMPA and NMDA receptor subunits) on cell surfaces, which are crucial for regulating synaptic function.

Neuronal Organization and Neural Circuits

Mu opioid receptors (MORs) are found throughout the brain, particularly in areas involved in addiction. The mesolimbic reward pathway, consisting of the ventral tegmental area (VTA) in the midbrain and the nucleus accumbens (NAc, or ventral striatum), is central to these effects. Activating MORs directly in the NAc creates pleasurable sensations. VTA dopamine (DA) neurons, which are crucial for reward, are controlled by GABAergic interneurons within the VTA and by GABA neurons from other MOR-rich regions, including the NAc, rostromedial tegmental nucleus (RMTg), and ventral pallidum. When opioids activate MORs, they reduce the release of GABA, an inhibitory neurotransmitter. This reduction in GABA activity then "disinhibits" VTA DA neurons, leading to their excitation and increased dopamine levels in the NAc, which contributes to the immediate rewarding effects of opioids.

The dorsal striatum, including the caudate and putamen, receives significant dopamine input from the midbrain and is vital for the habitual behaviors that develop with opioid abuse. Similar to other addictive substances, long-term opioid use disrupts glutamatergic processes, affecting synaptic plasticity. The prefrontal cortex (PFC), which includes the orbital frontal cortex (OFC), is involved in decision-making, evaluating rewards, and goal-directed behavior. It regulates subcortical areas like the NAc, dorsal striatum, and amygdala (Amyg) through glutamatergic signals. Increased activity in the PFC and NAc is observed in humans during drug craving. Studies in animal models show that the PFC-NAc circuit is involved in cue-induced relapse to heroin self-administration, along with increased glutamate levels in the NAc. The Amyg is also deeply involved in the emotional dysregulation of craving and the negative feelings often experienced during withdrawal.

From a clinical perspective, MOR agonists are important for pain relief because they can inhibit pain signals in the dorsal horn of the spinal cord. However, increasing opioid use due to tolerance and the use of highly potent drugs like fentanyl elevate the risk of overdose. These overdoses can be fatal because opioids inhibit the brainstem respiratory centers in the medulla and pons, which also contain many MORs.

Novel, Emerging Neurobiology

The disrupted regulation of the glutamatergic system observed with long-term opioid use is an expanding area of scientific investigation. Recent molecular findings indicate epigenetic changes in the striatum of individuals who abuse heroin. These changes are connected to a protein called Fyn, a non-receptor tyrosine kinase, which plays a role in regulating glutamatergic signaling and the structural organization of cells. Similar Fyn disruptions found in the striatal neurons of human heroin abusers are also seen in rodents that self-administer heroin. Heroin increases both the active (phosphorylated) form of Fyn and the phosphorylation (at Tyr-18) of its target protein, Tau, which is strongly associated with a decline in cognitive function. Human brain studies also highlight epigenetic impairments in genes related to synaptic plasticity and glutamatergic neurotransmission. These impairments significantly correlate with specific epigenetic markers, such as H3K27 acetylation, which shows a positive relationship with the duration of heroin use.

Conventional and Novel Theories for OUD Treatment

Current standard treatments for Opioid Use Disorder (OUD) involve substituting the opioid with another opioid that has lower potency and a longer half-life, such as methadone. This approach helps prevent periods of intense highs and severe withdrawal symptoms. Buprenorphine is also used clinically, often combined with naloxone (e.g., Suboxone). The naloxone component is designed to block the rewarding effects if the medication is misused by intravenous injection instead of being taken orally.

The development of novel opioid ligands is progressing, with efforts to target specific intracellular signaling pathways that might selectively influence the MORs' effects on reward, pain relief, and respiratory depression. For instance, G protein signaling and beta-arrestin recruitment are thought to mediate pain relief and respiratory suppression, respectively, while reward appears to be driven by GRK-5. This research suggests that "biased agonists," which stabilize MORs in a specific shape that activates only certain intracellular signaling pathways, could potentially provide strong pain relief without increasing the risk of addiction.

The need for non-opioid medications has also directed research towards the glutamatergic system. For example, a small molecule inhibitor of Fyn kinase has been shown to reduce heroin-taking behavior in preclinical animal models. Similarly, an inhibitor of acetylation epigenetic marks, which are linked to impaired glutamatergic signaling, has been found to decrease heroin self-administration. These and other emerging neurobiological discoveries related to OUD hold promise for developing new treatment strategies to significantly address the opioid epidemic and assist the millions affected by the disorder.

Acute Opioid Neurobiology

Opioid drugs vary in their strength, effectiveness, and how the body processes them at specific receptor sites. These sites include mu (MORs), delta (DORs), and kappa (KORs) opioid receptors, which are a type of inhibitory G protein-coupled receptor (GPCR). MORs and DORs are responsible for both the pain-relieving effects and the rewarding or addictive properties of opioids. KORs offer limited pain relief and can cause unpleasant side effects such as feelings of unease, anxiety, and hallucinations. MORs are the primary focus of most research related to opioid use disorder (OUD). When activated, MORs trigger a cascade of intracellular events, including the activation of Gai/o proteins, inhibition of cAMP, receptor internalization, phosphorylation by G protein receptor kinase (GRK), and the recruitment of beta-arrestin 2 (barr-2). These actions affect various downstream pathways, such as those involving enzymes, ion channels, and small GTPases, which regulate multiple signaling cascades like the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation pathway.

Common recreational opioids like heroin, and prescription opioids such as morphine, codeine, and oxycodone, fully activate MORs. High-potency synthetic opioids, such as fentanyl, are particularly rewarding and significantly increase the risk of opioid overdose fatalities. The effects of opioids and opioid overdoses can be counteracted by drugs like naloxone, which are high-affinity MOR antagonists. These antagonists work by displacing opioids from the receptors and inactivating them.

Chronic Opioid Neurobiology

Repeated use of opioids leads to tolerance, meaning the effects of the drug, such as pain relief and reward, become reduced. Consequently, higher doses are needed to achieve the same effects as before. Long-term opioid use also causes lasting changes in other neurotransmitter systems, including dopamine (DA), glutamate, and GABA, which contribute to altered synaptic plasticity. For example, sustained MOR activation can increase the number of glutamatergic receptors (AMPA and NMDA receptor subunits) on the cell surface, which are crucial for regulating how synapses function.

Neuronal Organization and Neural Circuits

MORs are found throughout the brain, including in regions strongly linked to addiction. The mesolimbic reward pathway, a key area for reward, involves the ventral tegmental area (VTA) in the midbrain and the nucleus accumbens (NAc), also known as the ventral striatum. Direct activation of MORs in the NAc creates pleasurable feelings. Dopamine neurons in the VTA, which are involved in reward, are regulated by GABAergic interneurons within the VTA and, to a greater extent, by GABA neurons from areas rich in MORs, such as the NAc, rostromedial tegmental nucleus (RMTg), and ventral pallidum. Opioid activation of MORs decreases the release of GABA, an inhibitory neurotransmitter, which in turn removes inhibition from VTA DA neurons. This leads to increased activity and higher dopamine levels in the NAc, contributing to the immediate rewarding effects of opioids.

The dorsal striatum, which includes the caudate and putamen, receives substantial dopamine input from the midbrain and plays a vital role in the development of habitual behaviors seen with opioid abuse. Similar to other addictive substances, chronic opioid use disrupts glutamatergic processes essential for synaptic plasticity. The prefrontal cortex (PFC), which includes the orbital frontal cortex (OFC), is involved in decision-making, evaluating rewards, and goal-directed actions. It exerts top-down glutamatergic control over subcortical areas like the NAc, dorsal striatum, and amygdala. In humans, activity in the PFC and NAc increases during drug craving. Consistent with this, the PFC-NAc circuit is implicated in cue-induced reinstatement behavior in animal models of heroin self-administration, coinciding with elevated glutamate levels in the NAc. The amygdala also heavily influences the emotional dysregulation of craving and the negative feelings often experienced during withdrawal.

Clinically, MOR agonists are important pain relievers because they can inhibit pain signals in the dorsal horn of the spinal cord. However, increasing opioid use as tolerance develops, along with the use of highly potent drugs like fentanyl, raises the risk of overdose. Overdoses can be fatal due to the inhibition of respiratory centers in the brainstem, specifically the medulla and pons, which contain many MORs.

Novel, Emerging Neurobiology

The disruption of the glutamatergic system observed with chronic opioid use is an expanding area of research. Recent molecular findings indicate epigenetic disturbances in the striatum of individuals who abuse heroin. These disturbances are linked to Fyn, a nonreceptor tyrosine kinase that regulates glutamatergic signaling and the structural organization of cells. Similar Fyn disturbances in striatal neurons of human heroin abusers have been replicated in rodents that self-administer heroin. Heroin increases both the active (phosphorylated) form of Fyn and the phosphorylation of its downstream target, Tau, which is strongly associated with neurocognitive decline. Studies of the human brain also highlight epigenetic impairments in genes related to synaptic plasticity and glutamatergic neurotransmission. These impairments significantly correlate with certain epigenetic markers, such as H3K27 acetylation, which shows a positive correlation with the number of years of heroin use.

Conventional and Novel Theories for OUD Treatment

Standard treatments for opioid use disorder (OUD) typically involve substituting the illicit opioid with another opioid that has lower potency and a longer duration of action, such as methadone. This approach helps prevent intense highs and severe withdrawal symptoms. Buprenorphine is also used clinically, often combined with naloxone (marketed as Suboxone) to prevent rewarding effects if the medication is misused intravenously instead of orally.

New opioid ligands are being developed to target distinct intracellular signaling pathways. The aim is to differentiate MORs' effects on reward, pain relief, and respiratory depression. For instance, G protein signaling is thought to mediate pain relief, while beta-arrestin recruitment is linked to respiratory suppression. Reward, on the other hand, appears to be driven by GRK-5. This research suggests that "biased agonists," which stabilize MORs in a specific conformation to selectively activate particular intracellular signaling cascades, could potentially offer powerful pain relief without increasing the risk of addiction.

The need for non-opioid medications has also shifted focus to the glutamatergic system. For example, a small molecule that inhibits Fyn kinase has been shown to reduce heroin-taking behavior in preclinical animal models. Similarly, an inhibitor of acetylation epigenetic marks, which are associated with impaired glutamatergic signaling, has been found to decrease heroin self-administration.

These and other new neurobiological discoveries relevant to OUD could lead to novel treatment strategies, potentially helping to significantly address the opioid epidemic and assist millions of individuals suffering from the disorder.

Acute Opioid Neurobiology

Opioid drugs vary in their strength and how they affect the body. They act on specific brain receptors, mainly mu (MORs), delta (DORs), and kappa (KORs). MORs and DORs are responsible for pain relief and the feeling of reward that can lead to addiction. KORs offer little pain relief and can cause negative feelings such as sadness, anxiety, and hallucinations. Most research on Opioid Use Disorder (OUD) focuses on MORs. When MORs are activated by opioids, they start a series of actions within brain cells, which affects various cell signals and pathways. Common opioids like heroin and prescription drugs (e.g., morphine, oxycodone) fully activate MORs. Stronger synthetic opioids like fentanyl are highly addictive and greatly contribute to fatal overdoses. Medications like naloxone can reverse opioid effects and overdoses by blocking MORs.

Chronic Opioid Neurobiology

Regular opioid use leads to tolerance, meaning the drug's effects, like pain relief and reward, become less potent over time. This requires individuals to take higher doses to achieve the same results. Long-term opioid use also changes how other brain chemicals, such as dopamine and glutamate, work. These changes affect how brain cells communicate and form connections. For example, constant activation of MORs increases the number of specific glutamate receptors on the surface of brain cells, which are key to cell communication.

Neuronal Organization and Neural Circuits

MORs are found widely in brain areas connected to addiction. The brain's reward system, called the mesolimbic pathway, includes the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Activating MORs in the NAc directly creates pleasant sensations. Reward-related VTA dopamine neurons are controlled by other brain cells that release GABA, a chemical that usually slows brain activity. Opioids activate MORs, which then reduce GABA release, causing VTA dopamine neurons to become more active. This increases dopamine in the NAc, leading to the immediate rewarding effects of opioids.

The dorsal striatum plays a key role in developing habitual behaviors seen in opioid abuse. Long-term opioid use also disrupts the brain's glutamate system, affecting how brain cells connect and adapt. The prefrontal cortex (PFC) helps with decision-making and goal-directed behavior. It influences deeper brain areas like the NAc and amygdala. Activity in the PFC and NAc increases during drug cravings. The amygdala is also important for managing emotions, especially negative feelings during withdrawal.

Opioid pain medicines, known as MOR agonists, are effective because they block pain signals in the spinal cord. However, as tolerance develops, people use higher doses, and the use of powerful drugs like fentanyl increases the risk of overdose. These overdoses can be deadly because opioids can stop breathing by slowing down brainstem areas like the medulla and pons, which contain many MORs.

Novel, Emerging Neurobiology

Researchers are actively studying how long-term opioid use disrupts the brain's glutamate system. New evidence shows that heroin use causes changes in how genes are expressed in the striatum, a brain area. These changes are linked to a protein called Fyn, which affects how brain cells signal using glutamate and how brain cells are organized. These Fyn-related changes seen in people who use heroin are also found in animal studies. Heroin increases the active form of Fyn and a related protein called Tau, which is involved in thinking and memory problems. Studies of the human brain also point to issues with gene expression related to brain cell connections and glutamate signaling, which become more pronounced with longer heroin use.

Conventional and Novel Theories for OUD Treatment

Current standard treatments for Opioid Use Disorder (OUD) involve using different opioids that are less strong and stay in the body longer, such as methadone or buprenorphine. Buprenorphine is often given with naloxone (Suboxone) to prevent the drug's rewarding effects if it's misused by injection instead of being taken orally. These treatments help manage withdrawal and cravings.

New opioid medications are being developed to target specific cell pathways. The aim is to create drugs that can relieve pain without causing addiction or stopping breathing. For example, researchers believe that different cell signals might control pain relief and breathing, while another signal causes the rewarding effects. This idea suggests that new drugs, called "biased agonists," could offer strong pain relief by activating MORs in a way that favors pain relief signals over addiction signals.

The search for non-opioid medications has also highlighted the glutamate system. For example, a drug that blocks the Fyn protein has reduced heroin use in animal studies. Similarly, another drug that affects gene expression changes linked to faulty glutamate signaling has also decreased heroin self-administration in animals. These new discoveries in brain science related to OUD could lead to new ways to treat the opioid crisis and help many individuals struggling with this disorder.

Acute Opioid Brain Science

Opioid drugs work in different ways and with different strengths at special spots in the brain called opioid receptors. There are a few kinds of these receptors, but the main one that causes pain relief and addiction is called the mu opioid receptor (MOR).

When common opioids like heroin, morphine, or oxycodone enter the body, they connect strongly with MORs. This connection sets off many actions inside brain cells. Powerful man-made opioids like fentanyl are especially good at this, which is why they are so addictive and can cause deadly overdoses. Luckily, medicines like naloxone can quickly reverse an overdose. Naloxone works by kicking the opioid off the MOR and stopping its actions.

Long-Term Opioid Brain Science

When a person uses opioids often, the body gets used to the drug. This is called tolerance. It means the person needs more and more of the drug to get the same pain relief or feeling they had before.

Long-term opioid use also changes how other important brain chemicals work. These changes can make brain cells act differently over time, which plays a role in addiction.

Brain Parts and How They Work with Opioids

MORs are found in many parts of the brain, especially in areas linked to addiction. One important area is the "reward pathway." When opioids activate MORs in this pathway, it causes a feeling of pleasure. Opioids do this by reducing the activity of some brain signals, which then causes other signals, like dopamine, to increase. This increase in dopamine is what creates the strong rewarding feeling.

Other parts of the brain also play a role. The area involved in forming habits becomes more active with ongoing opioid use. Another part helps with making choices and controlling behavior, but opioid use can disrupt this. A different brain area handles emotions and can cause strong cravings and bad feelings during withdrawal.

Opioids are good at stopping pain signals in the spinal cord, which is why they are used as pain medicine. However, using too much, especially very strong drugs like fentanyl, can be dangerous. Overdose can stop a person's breathing because opioids also affect brain areas that control breathing.

New Brain Science Discoveries

Scientists are learning more about how long-term opioid use changes the brain. Research shows that certain brain signals, like the glutamatergic system, are thrown off balance. There are also new findings about how genes and the structure of brain cells are affected.

For example, studies have found changes in a protein called Fyn in the brains of people who use heroin. These changes are also seen in animals given heroin. Heroin increases the active form of Fyn and another protein called Tau, which is linked to problems with thinking and memory. These discoveries suggest that opioid use can lead to lasting changes in the brain's genetic and cellular makeup.

Current and New Ways to Treat Opioid Use Disorder

Today, common treatments for opioid use disorder (OUD) include using other opioid medicines, like methadone or buprenorphine. These drugs are less powerful and stay in the body longer, helping to prevent extreme highs and withdrawal symptoms. Buprenorphine is often given with naloxone (called Suboxone) to prevent misuse.

New research is exploring different kinds of opioid drugs that could relieve pain without causing addiction or breathing problems. The idea is to create drugs that only activate certain good effects of the MOR, rather than all of them.

Scientists are also looking at non-opioid medicines. Some new treatments might target the brain's glutamatergic system or specific proteins like Fyn, which have shown promise in reducing heroin-seeking behavior in early studies. These new findings offer hope for developing better treatments to help people with OUD.