PAIN PATHWAYS AND OPIOIDS

Peripheral Afferents Conducting Pain and Temperature
A-delta fibers

• free (naked) nerve endings
• Myelinated
• Diameter = 1-4 nm
• Transmit "fast pain" or "first pain"
• well-localized discriminative sensation (sharp, stinging, prickling)
• duration of pain coincides with duration of painful stimulus

C fibers

• free (naked) nerve endings
• Unmyelinated
• Diameter = 0.4-1.2 nm
• Transmits "slow pain" or "second pain"
• diffuse and persistent burning, aching, throbbing sensation - dull, chronic
• duration of pain exceeds duration of stimulus

Classification of Pain

1. Somatic
2. Superficial (cutaneous)
3. Deep (from muscles, tendons, joints, fascia) - generally involves both first and second pain.
4. Visceral (arising from either parietal peritoneum or viscera itself) - second pain from viscera is carried by C fibers.  First pain from parietal peritoneium is carried by A-delta fibers

Dual Pain Pathways
Entry of A-delta and C fibers into the Posterior Cord
The "fast" and "slow" pathways are activated in the periphery when the free nerve endings of the A-d and C fibers are stimulated (damaged; nociceptors details painful stimuli).  The cell bodies of the A-d and C fiber afferents are found in the dorsal root ganglion.  The A-d and C fibers enter the dorsal cord, divide and ascend or descent 1-3 segments in the tract of Lissauer. 
Pain pathways are contralateral - they crossover then go up spinal cord.
(touch, pressure and proprioception are ipsilateral).

Transmission of Pain Impulses Through the Dorsal Horn
Pathway for fast-sharp pain: After leaving the tract of Lissauer, the axons of the A-d fibers enter the dorsal horn and terminate in Rexed's lamina I and lamina V.  Second order neurons leaving lamina I or lamina V cross to the contralateral lateral spinothalamic tract and ascend to the brain.

Pathway for slow-chronic pain: The C fibers terminate primarily in lamina II and also lamina III. Interneurons transmit C fiber impulses to lamina V from laminae II and III.  Neurons leaving lamina V cross immediately to the contralateral lateral spinothalamic tract and ascend to the brain.

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***KNOW (Valley):

• Sources differ: some say lamina II is the substantia gelatinosa, other sources say it is lamina II and III.
• The major neurotransmitter released from A-d fibers is glutamate which binds to AMPA and NMDA receptors on the postsynaptic membrane.  The normal ligand for NMDA is glutamate.
• The major neurotransmitter released from C fibers is substance P, which binds to NK-1 (neurokinin-1) receptors on the postsynaptic membrane.

Spinal Cord Tracts for Transmitting and Modulating Pain
The ascending sensory spinal cord tract carrying pain and temperature is the lateral spinothalamic tract, which is a component of the anterolateral sensory. The dorsolateral funiculus shown in figure below is a descending tract.   The function of the dorsolateral tract is to modulate pain (stop pain at the spinal cord)

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Anatomy of the Lateral Spinothalamic Tract
The lateral spinothalamic tract carries pain and temperature modalities.  C fiber afferents enter the spinal cord via the dorsal horn.  The C fibers synapse just after entering the spinal cord with interneurons in lamina II or lamina III.  The interneurons from laminae II and III synapse with second order neurons in lamina V.  Second order neurons leaving lamina V cross immediately to the opposite (contralateral) side in the spinal cord and then ascend on the contralateral side.

QUESTION:
If the right spinothalamic tract is severed at C3, what sensations are lost where?
Pain & temperature deficits on contralateral side (L) at all levels below the injury (C3)

What sensations are blocked in the lateral columns by epidural or spinal anesthesia?
Pain and temperature bilaterally

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The Substantia Gelatinosa: The Side where Pain Impulses are Attenuated (decreased)
The body's natural Analgesia
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The first neuron in the slow-chronic pain pathway synapses with the interneurons in the substantia gelatinosa (Rexed's lamina II) and lamina III of the spinal cord and releases the excitatory transmitter, substance P (SP) to these interneurons.  Enkephalin-releasing interneurons synapse on the substance-P releasing nerve terminal.  When enkephalin is released to the nerve terminal of the primary pain C fiber afferent, the release of SP is decreased.  When the release of SP is decreased, the number of action potentials initiated in the interneuron of the pain pathway is reduced and, ultimately, the perception of pain is decreased.  Enkephalin may be considered the "gate" in the gate control theory of pain.  There are many other modulators of pain transmission in the substantia gelatinosa (not discussed here).

Enkephalin - a neurotransmitter that is a nateral endogenous opioid --> Endorpins, Dynorphins.  The Enkephalin receptor on the Presynaptic C-fiber is the opioid receptor: Mu1, Mu2, Kappa, Delta.  All are present but Mu2 dominates in the SG.  Signal transduction in Mu receptor decreases the release of substance P.

Mechanism of Analgesia Produced by Neuraxial Opioids
Narcotic (Rx) produced Analgesia
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Opioids (morphine, fentanyl, sufentanil, alfentanil, etc.) stimulate the same receptors that are stimulated by the body's endorphins and enkephalins.  After an opioid is injected into the intrathecal or epidural space, it diffuses into the substantia gelatinosa (Rexed's lamina II) and unites with opioid receptors on the nerve terminal of the primary pain afferent.  The release of substance P is reduced, and transmission of impulses through the SG is inhibited.  This is spinal analgesia.  Mu1, Mu2, kappa and delta receptors mediate spinal analgesia.  Spinal opioid analgesia is mediated primarily by Mu2 receptors.

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Neuraxial (Intrathecal or Epidural) Placement of Hydrophilic Opioids
Morphine, a hydrophilic opioid, crosses lipid membranes slowly

Intrathecal Placement - after intrathecal (spinal) placement, morphine diffuses out of the intrathecal space slowly.  Onset of analgesia is slow and duration of analgesia is prolonged.  Early depression of ventilation does not occur because uptake by systemic circulation is minimal, but rostral spread of significant quantities of morphine in CSF causes late (6-12 hours) depression of ventilation (morphine trapped in CSF circulates to brainstem)

Epidural Placement - after epidural placement of morphine, onset of analgesia is slow and duration of analgesia is prolonged.  Because systemic uptake is greater when morphine is injected into the epidural space, early depression of ventilation (within 2 hours) may occur, although unlikely.  Late depression of morphine, again d/t rostral spread in CSF, occurs.

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Neuraxial (Intrathecal or Epidural) Placement of Lipophilic Opioids
Lipophilic opioids (fentanyl, alfentanil, sufentanil) readily diffuse through lipid membranes

Intrathecal Placement - diffusion of lipophilic opioid out of the CSF is rapid.  For lipophilic opioids, onset of analgesia is rapid and duration of analgesia is short.  Early depression of ventilation (within two hours) occurs because of significant systemic uptake.  Because diffusion of lipophilic opioids out of CSF is substantial, rostral spread is minimal and late depression of ventilation does not occur.

Epidural Placement - Injecting a lipophilic opioid into the epidural space produces responses similar to those seen after intrathecal injection.

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Side-Effects of Neuraxial Opioids:

• Pruritus
• Neonatal morbidity
• Nausea
• Sexual dysfunction
• Urinary retention
• Ocular dysfunction
• Depression of ventilation
• Gastrointestinal dysfunction
• Sedation
• Thermoregulatory dysfunction
• CNS excitation
• Water retention

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Spinal Analgesia

Spinal analgesia occurs when transmission of pain impulses through the substantia gelatinosa (Rexed's lamina II) is suppressed. Mu1, Mu2, Kappa, and delta receptors mediate spinal analgesia, although the dominant receptor mediating spinal analgesia is the Mu2 Receptor.  The patient's perception of pain is diminished by spinal analgesia; this makes sense because fewer action potentials are relayed to the brain when spinal analgesia occurs.  Opioids acting in a region of brain referred to as the periventricular/periaqueductal gray produce spinal analgesia.  Spinal analgesia results from the action of opioids in the substantia gelatinosa (after epidural or intrathecal administration) or in the periventricular/periaqueductal gray (after IV administration).  *Narcotics work on different regions depending on how you administer them*.

Spinal analgesia can be produced starting in centers above the spinal cord (periventricular gray, periaqueductal gray, locus ceruleus, raphe magnus nucleus).  Do not call this supraspinal analgesia - the net action is analgesia at the spinal cord level (substantia gelatinosa).

Supraspinal Analgesia

Supraspinal analgesia occurs when opioids act in the brain at sites including the limbic system, hypothalamus, and thalamus.  Supraspinal analgesia is medited by Mu1, kappa and delta receptors, although the dominant receptor mediating supraspinal analgesia is Mu1.  With supraspinal analgesia, the patient's response to pain is altered, "I feel the pain, but I don't care"  Supraspinal analgesia develops after IV administration of opioids only.  Euphoria.

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Modulation of Pain - Brain Control of Substantia Gelatinosa (Spinal Analgesia)
Descending neurons originating in the periventricular and periaqueductal gray terminate on enkephalin-releasing interneurons in Rexed's lamina II (substantia gelatinosa).  The enkephalin released from the lamina II interneurons attaches to the receptors of the nerve terminal of the C fiber afferent and inhibits that release of substance P.  Spinal analgesia results. 
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Mechanisms of Modulation of Pain by Descending Spinal Cord Tracts
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