AKA Afferent Neuron

• The primary (first) afferent neuron is the nociceptor
• The cell body of the nociceptor is in the dorsal root ganglia (DRG) and the nociceptors synapse with the secondary neuron in the dorsal horn (DH) of the spinal cord
• The secondary neuron synapses with the tertiary neuron in the thalamus
• The tertiary neurons go to the cortex where pain perception occurs
• Pain information is processed in cortex

AKA Efferent

• Neurons beginning in the cortex make the first synapse in the brainstem
• The next neuron in the descending pathway makes a synapse with the ascending pathway in the spinal cord
• The descending neuron input modulates the ascending pain sensory pathway
• Modulation by the descending pathways results in enhancement or reduction of pain perception

• ASIC
• P2X
• P2Y
• B1
• B2

• TRPV1
• TRPV2

• Increased Na+ and Ca2+ influx
• Generator potential (membrane depolarization)
• Voltage-gated sodium channel threshold is reached
• ACTION POTENTIAL!

• Glutamate
• CGRP
• Substance P

• Ionotropic receptors
• NMDA-R, AMPA-R

• Metabotropic Receptors
• mGluR, NK1, CGRP-R

Gi-Coupled Protein Receptor

• Decreased cAMP
• Decreased presynaptic [Ca2+]i --> prevents vesicular exocytosis of neurotransmitters
• Opening of postsynaptic K+ channels (efflux)

• The site of noxious stimuli in the periphery
• The synapse between the primary and secondary neuron in the spinal cord
• The synapse between the secondary and the tertiary neuron in the thalamus

1. Metabolic
2. Intracellular Signaling Involving Gi-CPR
3. NMDA Receptor Signaling

• Occurs due to increased metabolic rate of the drug
• Log plasma concentration falls at faster rate with accelerated metabolism

Mechanism of Tolerance: Intracellular Signaling Involving Gi-CPR

ACUTE

• The binding of opioid receptor causes direct inhibition of AC and opening of K+ channels through G-alpha-i-GTP
• Low AC activity results in decrease cAMP, which in turn results in decreased PKA activity
• Decreased PKA activity results in closure of Na+ channels

Mechanism of Tolerance: Intracellular Signaling Involving Gi-CPR

CHRONIC

• After chronic administration of an opioid, CREB becomes activated (phosphorylated) which increases expression of AC above baseline
• As a result of increased levels of AC, levels of cAMP return toward baseline
• PKA activity opens Na+ channels
• K+ channels are not affected

• Activation of NMDA receptor by glutamate induces the activation of NO synthase
• NO complexes with guanylyl cyclase and activates GC
• NO also S-nitrosylates proteins, including subunit 1 and subunit 2 of the NMDA receptor
• NO is converted to peroxynitrate which will nitrate tyrosine residues with proteins
• All of these actions result in opiate tolerance

First pass metabolism

Mu receptor selectivity

Antitussive

Demethylated to morphine

Long half-life = withdrawal symptoms less severe

Detoxification for heroin addicts

Less analgesic potency than morphine

For moderate to severe pain

Metabolite (normeperidine) can cause seizures

Monoamine reuptake blocking activity

Warning with MAOI use -- Serotonin Syndrome

Far less analgesic potency and much less adverse effects  than methadone

For mild pain

Very potent

Faster onset and recovery than morphine

Similar side effect profile as morphine

For moderate to severe pain

Agonist at Kappa, Antagonist at Mu

Effective for moderate to severe pain

Higher doses increase BP and HR

Agonist at Kappa, Antagonist at Mu

Effective for moderate to severe pain

Kappa Agonist, Mu Antagonist

Similar analgesic potency as morphine

Reaches maximal (ceiling) analgesic and respiratory depression effect

For moderate to severe pain

Mu Partial Agonist, Kappa Antagonist

Slowly dissociates from Mu receptor

Used in opioid addiction management

Reverse (Inverse) Mu Agonist Activity

Few effects when administered alone

Causes withdrawal

Reverses toxicity

Used for overdose

Reverse (Inverse) Mu Agonist Activity

Few effects when administered alone

Causes withdrawal

Reverses toxicity

Used for overdose

Reverse (Inverse) Mu Agonist Activity

Few effects when administered alone

Causes withdrawal

Reverses toxicity

Used for overdose

Non-Opioid

Blocks N-Type Ca2+ Channel -- a type of HVA channel found presynaptically

For severe chronic pain

P2X

P2Y

B1

B2