Opioid Receptors and Pain

Opioid Receptors

• Multiple opioid receptors exist in the body.
• These receptors are usually named after the substance that was discovered to activate them, which is a common practice.
• Opioid Receptors regulate a wide range of processes, including: pain perception, reward-seeking behaviors, hedonic pleasure, and respiration.
• Endogenous opioids, also known as endorphins, activate opioid receptors.

Opioids/Opiates

• Opiates are naturally occurring substances derived from the opium poppy.
• They are active agents in clinically used medications and illegal recreational drugs.
• Opioids is the general term that includes naturally produced opiates from opium poppies and synthetic substances with the same mechanism of action.
• Examples of opioids include: Morphine, Heroin, Fentanyl, Codeine, Oxycodone.
• Opioids are agonists for opioid receptors, meaning they activate the receptor when they bind.

Pain

• Pain is encoded by a subdivision of sensory neurons in the Peripheral Nervous System (PNS).
• Axons carry pain information from the body to the Central Nervous System (CNS).
• Pain is a useful tool for avoiding harmful stimuli, being aware of possible body damage, and learning.

Endogenous Opioid Pain Suppression

• Suppressing pain perception is important for certain survival situations, such as running from danger.
• Some neurons with opioid receptors inhibit the signaling of pain receptors.
• When endogenous opioids activate these receptors, pain sensory neurons are inhibited, temporarily reducing or eliminating pain perception.

Opioids and Pain

• The primary clinical use of opioid drugs is pain management.
• Opioids work by taking advantage of the pain suppression signaling of endogenous opioids.
• Opioid drugs bind to opioid receptors, which effectively and efficiently inhibits pain sensory neurons.
• Opioids block pain signals from reaching the brain, resulting in a lack of pain perception.

Opioids - Pain Management

• Opioids are an important tool to help people mitigate pain due to injury, disease, or medical procedure recovery.

Double-Edged Sword

• Opioid drugs activate all the opioid receptors across the body, and do not act on only pain receptors.
• This leads to other side effects.

Tolerance

• Endogenous opioid receptors in the brain modulate multiple cognitive processes like hedonic pleasure, reward-seeking behavior, and play behaviors.
• Endogenous opioids are released in small quantities.

Opioid Drugs in the Brain

• Opioid drugs interact with all opioid receptors in the brain and body, which influences psychological and physiological processes.
• The concentration of opioid drugs is considerably larger than naturally released endogenous opioids.

Acute Effect of Opioids

• Opioid drugs oversaturate synapses and greatly activate opioid receptors.
• This leads to changes in behavior and perception: analgesia, euphoria, and reward seeking behaviors.
• Short-term behavioral and perceptual changes are typically the desired outcome for opioid users seeking pain suppression or euphoria.

Homeostasis

• Extreme activation of opioid receptors is a deviation from the normal, and the body will want to maintain homeostasis.
• The body will modify neural structures to adapt to abnormal stimuli.

Long-Term Effects of Opioids

• The synapse will want to return to basal activation levels and neurons will detect the over activation of opioid receptors.
• Opioid receptors are removed from the membrane, leading to a weaker response to the same amount of ligand.

Tolerance

• To obtain the same effect, the drug dosage must be increased.
• A higher dose causes over activation of synapse, which results in more synaptic changes.
• The decrease of receptors impacts both opioid drugs and endogenous opioids.
• Opioid receptor mediates behaviors that will be suppressed following tolerance, leading to: increased pain sensitivity, decreased hedonic pleasure, and decreased reward seeking behaviors.

Recovery

• Recovery is unclear if the synapses return to how they were before tolerance.
• Complete recovery could take years, but the major drive for relapsing for people with substance use disorder.

Opioids and the Reward Pathway

• Neural adaptations due to opioid drugs change synaptic communication in the brain's reward pathway.
• Changes in the reward pathway will significantly influence behavior.

Reward Pathway

• The reward pathway is a series of brain areas important for regulating reward seeking behaviors, where Dopamine (DA) is produced in the Ventral Tegmental Area (VTA).
• The Ventral Tegmental Area (VTA) is one of the multiple DA producing regions in the midbrain.
• Axons from the VTA project to the nucellus accumbens (NA) and the cortex.
• The pathway is most active during behaviors associated with motivation and reward seeking behaviors

Dopamine Misconceptions

• Dopamine (DA) is commonly referred to as the "happiness" molecule and is not fully responsible for feeling "happy."
• Drugs that result in experiencing euphoria activate DA neurons.
• Dopamine might be an aspect, but not the major signaling molecule

DA Reward Experiment

• Recording from the DA producing cells of the Ventral Tegmental Area (VTA) in mice and examining activity when a reward is unexpectedly received.
• APs fire when DA is released.

DA Reward Experiment - Results

• Ventral Tegmental Area (VTA) cells are active when receiving an unexpected reward or when a cue associated with reward is presented.
• Ventral Tegmental Area (VTA) cells are not active when receiving an expected reward.
• Dopamine (DA) signaling is not crucial for enjoying a stimuli or is crucial for wanting and reward seeking behavior.
• Dopamine encodes for learning about rewarding stimuli and responding to information associated with a reward.

"Liking" Signaling

• Dopamine does not exclusively mediate "liking" or hedonic pleasure.
• Most likely a complex interaction amongst opioid receptors, endocannabinoid receptors, and Dopamine (DA) receptors.

Reward Pathway Physiology

• The Nucellus Accumbens (NA) has Dopamine (DA) and opioid receptors to mediate reward seeking behaviors.
• Release of endogenous opioids will enhance the activity of DA axons.
• Opioid receptors inhibit an interneuron, reducing its inhibition of the DA axon, and increasing Dopamine (DA) release

Opioids in Reward Pathway

• Activation of opioid receptors will enhance DA signaling, encoding rewarding stimuli.
• Opioids oversaturate opioid receptors on interneurons, greatly inhibiting interneurons.
• DA synaptic signaling is greatly enhanced.
• The Nucellus Accumbens (NA) will encode opioid stimuli as an extremely rewarding experience.
• DA release will be significantly more salient than non-opioid stimuli, motivating repeated exposure to the opioid stimuli.
• Behaviors will prioritize experiencing more opioid stimuli over things like food or social interactions.

Tolerance in the Reward Pathway

• The Nucellus Accumbens (NA) will experience opioid tolerance with high or chronic doses of opioids
• There are fewer opioid receptors on the interneurons, which are less sensitive to opioid drugs and endogenous opioids.
• Leads to increased inhibition on Dopamine Cell (DA).
• Non-opioid stimuli is even less "rewarding"
• Same number of endogenous opioids activating significantly fewer opioid receptors
• Opioid stimuli will be more "rewarding" if opioid doses are increased
• Increased number of opioids to activate the decreased number of opioid receptors

Reward Pathway Changes

• Brain structures responsible for reward seeking are re-wired.
• Behavior changes to prioritize experiencing opioid stimuli over non-opioid stimuli.
• As tolerance increases, drug seeking behaviors increase, creating a positive feedback loop.

Substance Use Disorder

• Addiction is a result of changes in neuroanatomy and behaviors resulting in physical and psychological dependence on opioid drugs.
• Addiction is recontextualized as a disease model, rather than personal choice.
• Neurological changes can occur due to few large dose exposures or chronic exposures.

Naloxone

• Opioid receptors are important for regulating respiration.
• Activation of opioid receptors suppresses breathing and is important for parasympathetic responses.

Opioid ODs

• Deaths due to opioid overdose (OD) are typically due to asphyxiation following over suppression of the respiratory system.
• Increased doses following tolerance increase the likelihood of overdosing.

Naloxone

• Naloxone, commercially known as Narcan, is an opioid receptor antagonist that counteracts the immediate effects of opioids, and can be administered to revert respiratory arrest due to opioid OD.
• Naloxone will block opioid receptors across the whole body, and will not undo the neurological changes that influence behaviors.

Opioid Research

• Opioid Research is a major field to better understand the mechanisms and risk factors for substance use disorder, and the development of non-addictive opioids for clinical use, and recovery from opioid mediated synaptic changes

This lesson explores opioid receptors, their function in regulating pain perception, reward, and respiration. It also looks at opioids and opiates, substances that activate these receptors, including morphine, heroin, and fentanyl. Pain is encoded by sensory neurons in the peripheral nervous system.