Lecture 12: Pain and Opioid Analgesics

Question 1

Definition of pain

Answer 1

Unpleasant sensory and emotional experience associated w real or potential tissue damage or described in terms of tissue damage

Question 2

2 components of pain pathways

Answer 2

• Peripheral nociceptive afferent neurons, which is activated by noxious stimuli
• Central mechanisms by which afferent input generates a pain sensation

Question 3

Aδ fibers

Answer 3

• Myelinated
• 1-5μ diameter
• Fast conductance (5-30m/s)
• Fast localized rapid pain conduction
• Activated by mechanosensitive and temperature sensitive

Question 4

C fibers

Answer 4

• Unmyelinated
• 0.1-1.5μm diameter
• Slow conductance (<1m/s)
• Mechanosensitive, temperature sensitive and chemical (capsaicin)

Question 5

How can conduction in pain pathways be selectively blocked, and what makes Aδ fibers and C fibers prone to different types of interference?

Answer 5

• Conduction in pain pathways can be selectively blocked.
• Aδ fibers are prone to noxia, while C fibers are prone to being blocked by local anesthetics.
• Knocking out both A and C fibers leads to the absence of pain, seen in certain developmental disorders.

Question 6

Why does the pain pathway have both fast (Adelta fibers) and slow (C fibers) components, and what is the functional significance of this distinction?

Answer 6

• Both fibers release glutamate n neuropeptides
• Fast pain, conducted by Adelta fibers, facilitates rapid withdrawal and helps limit tissue damage.
• Slow pain, carried by C fibers, serves to immobilize the affected area, allowing time for healing and recovery.
• Dual system provides an adaptive response to different types of noxious stimuli and contributes to the overall protective mechanisms of the body.

Question 7

Describe the pathway of the spinothalamic tract

Answer 7

• Begins with sensory neurons located in the dorsal root ganglion (DRG), where pain fibers enter the dorsal horn of the spinal cord
• From there, fibers ascend through the white matter of the spinal cord, reaching the thalamus where they synapse.
• The signals are then relayed to the sensory cortex.
• In the head, most pain fibers originate from the trigeminal nuclei, entering at the level of the brainstem.

Question 8

Describe the organization of the spinal cord and the role of lamina 2 in pain transmission

Answer 8

• The spinal cord is organized into laminated layers.
• Small afferent nerve fibers, which mainly carry pain signals, synapse into lamina II (AKA substantia gelatinosa)
• This region is crucial in processing pain signals and is a target for analgesic medications aiming to alleviate pain. Additionally, pain signals can ascend segments of the spinal cord to cross over to the other side.

Question 9

What is the gate theory of pain?

Answer 9

• Mechanism in the spinal cord
• Pain signals can be sent up to the brain to be processed to accentuate the possible perceived pain, or attenuate it at the spinal cord itself.
• Gate: mechanism where pain signals can be let through or restricted.
• If you activate other fibers that can prevent pain impulses from going into the brain
• Distractive stimuli activates sensory fibers that carry the information into the brain
  
  • Activate inhibitory interneurons within the spinal cord, which acts to reduce the pain’s signal
• Can only let certain sensations thru at one time
• If you activate other sensory neurons, you prevent the pain from going thru the gap

Question 10

What is the descending pathway?

Question 11

What is the periaqueductal gray (PAG) and its role in pain modulation?

Answer 11

• PAG: region of cells surrounding the aqueduct in the midbrain, which is the central duct connecting the spinal cord to the brain
• Stimulation of the PAG has been shown to produce inhibition of pain, effectively reducing the sensation of pain.
• This region is involved in analgesic pathways, where it can modify how pain is felt.
• By activating pathways that descend from the PAG, it is possible to inhibit pain signals, offering a potential mechanism for pain management and the action of certain analgesic drugs.

Question 12

What are analgesics?

Answer 12

• Local anesthetics: block nerve conduction
• General anesthetics
• Non-steroidal anti-inflammatory drugs (NSAIDS)
  
  • E.g. aspirin, ibuprofen
• Opioids (morphine)

Question 13

What are opiate analgesics (opioids)?

Answer 13

• Potent analgesic
• Opia: naturally occurring substance
• Opioid: refers to both opiates n synthetic substances
• Strict activity relationships [receptors]
• Compounds are of similar structures
• Morphines are archetypal

Question 14

What are the CNS effects of opioids?

Answer 14

• Profound anaglesia w/o loss of consciousness
  
  • Good for acute n chronic pain
  • Not so good for neuropathic pain (difficult to treat)
• Respiratory depression
  
  • Reduce breathing by reducing sensitivity to PCO2
  • Causes to die w overdose
• Nausea n vomiting
  
  • Activates chemotrigger zone (medulla)
  • Disappears w repeated administration (tolerance)
• Euphoria, contentment and wellbeing
• Dry mouth
• Drowsiness/lethargy
• Pholcodeine: depression of cough reflex
• Pupillary constriction: stimulation of oculomotor nucleus

Question 15

How does an opioid drug affect sensitivity to carbon dioxide?

Answer 15

• Opioid drugs can reduce sensitivity to carbon dioxide in the body.
• Normally, carbon dioxide levels in the blood drive the breathing process.
• However, opioids can shift the carbon dioxide response curve, making the body less sensitive to increases in carbon dioxide levels → stop breathing even when carbon dioxide levels rise, → respiratory depression.

Question 16

Effect of opioids on the GI tract

Answer 16

• Increases tone n reduces gut motility
• Constipation
• Delays gastric emptying → slows drug absorption

Question 17

What effect does opioid have on the direct release of histamine from mast cells?

Answer 17

• Urticaria (hives)
• Bronchoconstriction (bronchospam), hypotension

Question 18

How do opioid antagonists work?

Answer 18

• Reverses the effect of opioid analgesics
• Suggestion that there was a receptor is bc opioid effects are reversible w an antagonist/inactive derivative
• Strict structure-activity relationships is consistent w receptors (unlike anesthetics)
  
  • Can predict the potency of the drug by their structures
  • GA has various structures

Question 19

How was the first opioid receptor discovered, and who conducted the study?

Answer 19

• Found an opioid receptor thru ligand binding
  
  • Opiates labelled w radioisotopes n bound to brain membrane homogenates
• Used 3H-levorphanol
• Candace Pert n Solomon H. Snyder
  
  • Published first binding study of what would turn out to be the µ opioid receptor using 3H-naloxone
  • Derivatives of morphine
  • Found the binding curve
  • Can get specific binding to a receptor
  • CONCLUSION: first definitive evidence that there was a receptor for opioids in the brain (endogenous)

Question 20

How do opioid analgesics affect gut contractions?

Answer 20

• Opioid analgesics (e.g. morphine) reduce gut contractions by acting on their receptors in the intestine.
• This effect can be antagonized by naloxone, which blocks the action of opioids.
• Studies have shown that different opioid analgesics have similar potencies in reducing gut contractions
  
  • Observed in both guinea pig ileum assays and human responses.
  • Methodology
    
    • Ground up the brain
    • Fractionated it
    • Tested the various fractions on his assay
    • 2 criteria: inhibit contractions like morphine AND reversible by naloxone

Question 21

Where are opioid peptides distributed in the brain and periphery?

Answer 21

• Areas associated w nociception: PAG, rostral ventral medulla n substantia gelantosa
• Enkephalins: diffuse distribution → suggests they play a role in many processes
• β-endorphins: less diffuse distribution
  
  • Primarily found in the hypothalamus, which projects to the PAG and noradrenergic nuclei in the brain stem.
  • Also found in periphery in adrenal medulla, heart, kidney (unclear role)

Question 22

What is the role of endogenous opioid peptides?

Answer 22

• Modulate pain perception
• Reward
  
  • Do smtg good -> release enkephalins n endorphines
• Stress response
• Autonomic control
• Activating opioid receptors
• Opioid analgesics work thru the endogenous opioid system replacing or supplementing the endogenous ligands

Question 23

How do the effects of morphine and enkephalins differ in the guinea pig ileum and vas deferens?

Answer 23

• Guinea pig ileum: morphine more effective than enkephalins in inhibiting contractions; this effect is blocked by naloxone
• Vas deferens: enkephalins are more effective than morphine; effect is weakly blocked by naloxone.

Question 24

What does the observation of cross-tolerance and withdrawal symptoms suggest about opioid receptors?

Answer 24

• Different opioid receptors may mediate distinct effects in different tissues
• Indicates that opioid receptors are involved in various physiological processes and may have differential sensitivities to different opioid agonists.

Question 25

Distribution of opiate receptor, MOP

Answer 25

• CNS n periphery
• Cortex, thalamus, PAG, RVM, substantia gelantinosa

Question 26

Distribution of opiate receptor, KOP

Answer 26

Hypothalamus, PAG, substantia gelantinosa

Question 27

DOP

Answer 27

Pontine nuclei, amygdala, olfactory bulb, cortex

Question 28

Describe the cellular actions of opioid receptors

Answer 28

• Opioid receptors are GPCRs
• Upon activation, they inhibit calcium channels, activate potassium channels, and inhibit the production of cAMP

Question 29

How are opioid peptides stored and activated within cells?

Answer 29

• Opioid peptides are initially stored as larger pro-molecules.
• The active components are cleaved off from these precursor molecules.
  
  • Examples include proenkephalin and proopiomelanocortin.

Question 30

Mechanisms of Pain Modulation

Answer 30

• Opioids exert their analgesic effects by activating descending inhibitory pathways that originate from the PAG region of the midbrain.
• Activation of opioid receptors in the PAG leads to the release of endogenous opioid peptides, such as endorphins and enkephalins, which act on opioid receptors located on neurons in the rostral ventromedial medulla (RVM).
• Neurons in the RVM send inhibitory projections to the dorsal horn of the spinal cord, where they inhibit the transmission of pain signals from primary afferent neurons.

Question 31

Tolerance

Answer 31

• Increase in the dose required to produce a pharmacological effect
• Occurs within a few days
• Tolerance occurs to: analgesia, emesis, euphoria, respiratory depression
• Addicts can take up to 50 times normal analgesic dose
• No/little tolerance to constipation and pupil constriction

Question 32

Dependence

Answer 32

• Craving that develops as a result of a repeated administration of the drug
• Psychological dependence outlasts physical withdrawal symptoms

Question 33

Characteristics of Morphine Analogues

Answer 33

• Half-life of 3-6 hours
• Erratic absorption orally
• Hepatic metabolism (conjugation with glucuronide). Some metabolites still active.
• Most excreted in urine, a proportion via the gut (enterohepatic cycling)
• Used on demand (infusion pump, PCA)

Question 34

Characteristics of Fentanyl

Answer 34

• Acute pain and anesthesia
• Patient-controlled infusion systems for chronic pain
• Highly potent (about 100X morphine)
• Rapid onset and short duration
• Recently used to cut heroin and cocaine
• Linked to many addict deaths (50,000 in USA, 2016)

Question 35

Characteristics of Codeine

Answer 35

• Methyl ester of morphine
• Naturally occurring in opium
• Weaker analgesic than morphine (1/6 to 1/15 strength of morphine)
• Less respiratory depression than morphine
• Less liable to produce constipation
• Often combined with paracetamol (co-codamol)

Question 36

Characteristics of Pethidine (Meperidine)

Answer 36

• Short-lasting analgesia
• Less potent than morphine
• Anti-muscarinic effects (dry mouth, blurring of vision)
• Duration similar to morphine
• Less constipating than morphine
• Analgesia during labor: does not reduce force of uterine contractions
• Slow elimination in neonates may require naloxone (antagonist)

Question 37

Characteristics of Methadone

Answer 37

• Used for chronic pain management and maintenance of addicts
• Can be administered orally or via injection
• Long half-life (greater than 24 hours)
• Produces little euphoria and less sedation compared to morphine
• Slow recovery attenuates withdrawal symptoms
• Further information on addiction will be covered in a later lecture

Question 38

Opioid Antagonists: Nalorphine, Naloxone, Naltrexone

Answer 38

• Competitive antagonists (except Nalorphine)
• Useful for treating opioid overdose
• Used to reverse respiratory depression in babies
• Precipitate withdrawal symptoms in addicts (further information in later lectures)

Question 39

Buprenorphine (Temgesic)

Answer 39

• Partial agonist at Mu Opioid Receptors (MOP)
• Administration routes: Sublingual, injection, intrathecal
• Inactive orally due to high first-pass metabolism
• Half-life approximately 12 hours
• Similar effects to morphine but with less respiratory depression
• Useful for chronic pain and opioid dependence (in the USA)
• Can precipitate withdrawal in patients dependent on morphine (further details in later addiction lectures)