Lec 39

True or False, there are multiple factors affecting pain perception.

True

Gender, genetics, medication, anxiety, Age

Acute Pain

Results from activation of pain receptors at the site of tissue damage

Cause: traumatic injury. surgery, inflammatory

Usually resolves in days to weeks

Serves as a warning signal to prevent further damage

Chronic Pain

Results from abnormal processing of stimuli from nerve damage

Typically lasts over 3 months to years

Cause fatigue, sleepiness, anxiety, stress, depression

Ascending/Afferent pathway

Carry signal from pain receptors to spinal cord and brain

“incoming nerves”

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1)Tissue damage → release of mediators

2)Stimulation of nociceptors, generating an action potential

3)Impulse travels along peripheral afferent nerves

4)Travels to dorsal horn of spinal cord→ brain stem→thalmus→limbic system

5) message is processed as painful

A delta fibers

Afferent fibers

thinly myelinated

Associated with sharp, immediate pain and responsible for the pulling away reflex

C fibers

Afferent fibers

unmyelinated

Responsible for slow, dull, longer lasting pain

Efferent/Descending pathway

Carry signal from brain and spinal cord to effector organs and muscles

“outgoing nerves”

Understand Gate Control Theory and the significance of the periaqueductal gray area.

Efferent pathway

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Non painful stimuli can close the gate to painful stimuli in the Periaqueductal Gray Area

(ex: rubbing an bumped elbow reduces pain)

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Stimulation of PAG activates enkephalin releasing neurons which modulates pain signal like volume control

Understand the SAR of the endogenous opioid peptides.

Endorphins and Enkephalins

Tyr-Gly-Gly-Phe

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Phenol and amine functional groups are most important

Understand the message-address concept of the endogenous opioid peptides.

The N terminus of a peptide contains the message→ First 4 amino acids conserved and essential for binding to all opioid receptors (knows to go to opioid recetpor)

Tyr-Gly-Gly-Phe

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The C terminus is the address, tells us what kind of opioid receptor

Additional amino acids in the sequence determine subtype specificity

opioid receptors are….

inhibitory GPCRs and that stimulation of them hyperpolarizes the neuron and terminates pain signaling.

Know the effect of opioid receptor stimulation on adenylate cyclase, cAMP, potassium flux, calcium flux and phospholipase C.

Inhibit adenylate cyclase which drives down cAMP concentrations

Activate inwardly rectifying K+ channels towards resting potential (increases K+ efflux)

Closes Ca2+ channels

Stimulates phospholipase C

Know that there are three classes of opioid receptors and their names.

Delta Opioid receptor→ enkephalins, B endorphin

Kappa opioid receptor→ Dynorphins, B endorphin

Mu opioid receptor→ Endomorphins, B Endorphin

What therapeutic action are mu-1 receptors associated with?

mediate pain neurotransmission

What side effect are mu-2 receptors associated with?

control respiratory depression

What would be the therapeutic advantage to the development of a selective kappa agonist?

Lack respiratory depression, constipation and physical dependence

Know the difference between tolerance and dependence

Tolerance: increasingly larger doses are required to produce the same degree of biological response

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Dependence: Opioid is necessary to maintain physiologic and psychological functioning

withdrawal and addiction.

Withdrawal: tremor, chills/sweats/increased blood pressure and heart rates, abdominal cramping

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Addiction: Due to euphoric effects produced by mu opioids, addiction is a significant challenge, complicated by psychosocial and genetic components

Know the challenges associated with the therapeutic use of opioids.

Euphoria/Dysphoria

Constipation

Cross tolerance (if swapping must be same type of opioid)

Metabolism

Combined alcohol consumption

Know the SAR of multicyclic opioid AGONISTS.

R1 group dictates control of agonist or antagonist activity→ methyl group tends to be agonist, 3-5 carbon chains tend to be antagonists

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Basic nitogren attached to R1 (tertiary amine)

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R2 H or methyl

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A ring is essential

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R3 is H or OH

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IMpact of R4 depends on presence of C7 and C8 double bond

What drug properties are relevant to choosing the appropriate opioid therapeutically?

Lipophilicity

Half life

Bioavailability

Excretion

Duration

heroin & morphine

Heroin is a prodrug that hydrolyzes into 6MAM which hydrolyzes to morphine

Can heroin cross the BBB?

Heroin is a prodrug, its active metabolite is morphine

Heroin is more lipophilic than morphine so it has better BBB access