Pain: Pathways, Fibers, and Neurotransmitters

Pain is part of life:

1. Overview of Pain

Pain is a protective sensory signal indicating potential or actual tissue damage. It is transmitted through specialized nerve fibers and processed by the central nervous system.

Types of Pain

1. Nociceptive Pain – caused by actual tissue damage.

   • Somatic: sharp, localized (skin, muscles, joints)

   • Visceral: dull, diffuse (organs)

2. Neuropathic Pain – caused by nerve damage.

3. Inflammatory Pain – due to tissue inflammation, sensitizing nociceptors.

2. Pain Pathways

Pain is transmitted through ascending (afferent) pathways to the CNS and modulated by descending pathways.

A. Peripheral Pain Transmission

1. Nociceptors – free nerve endings responding to:

   • Mechanical stimuli (pressure, stretch)

   • Thermal stimuli (extreme heat or cold)

   • Chemical stimuli (inflammatory mediators)

2. Primary Afferent Fibers

   • A-delta fibers:

     • Myelinated → fast conduction (5–30 m/s)

     • Transmit sharp, localized, “first” pain

     • Synapse in dorsal horn (lamina I and V)

   • C fibers:

     • Unmyelinated → slow conduction (0.5–2 m/s)

     • Transmit dull, burning, “second” pain

     • Synapse in dorsal horn (lamina II – substantia gelatinosa)

B. Dorsal Horn Processing

• Primary afferents release neurotransmitters to secondary neurons:

  1. Glutamate – fast excitatory transmission via AMPA/NMDA receptors.

  2. Substance P – slower, modulatory signal enhancing pain transmission.

• Interneurons in lamina II modulate pain via GABA and glycine (inhibitory).

C. Ascending Tracts

1. Spinothalamic Tract (anterolateral system)

   • Lateral spinothalamic → pain & temperature

   • Ventral spinothalamic → crude touch & pressure

   • Projects from dorsal horn → thalamus → somatosensory cortex

2. Spinoreticular Tract

   • Contributes to emotional/affective response to pain

3. Spinomesencephalic Tract

   • Projects to periaqueductal gray (PAG) for pain modulation

3. Sympathetic Involvement

• Visceral pain often involves sympathetic fibers:

  • Pain signals from organs travel via preganglionic sympathetic fibers → dorsal root ganglion → spinal cord

• Preganglionic fibers: cholinergic (acetylcholine)

• Postganglionic fibers: mostly adrenergic (norepinephrine)

• Neurotransmitters involved in pain modulation:

  • Substance P, CGRP (calcitonin gene-related peptide) – excitatory

  • Glutamate – excitatory

  • GABA & Glycine – inhibitory

  • Endorphins / Enkephalins – endogenous opioid modulation in descending pathway

4. Descending Pain Modulation

• CNS can inhibit or facilitate pain through descending pathways:

  1. Periaqueductal gray (PAG) → Rostral Ventromedial Medulla (RVM) → spinal cord dorsal horn

  2. Neurotransmitters:

     • Serotonin (5-HT)

     • Norepinephrine

     • Endogenous opioids (endorphins, enkephalins)

• Outcome: inhibits primary afferent transmission at dorsal horn, reducing pain perception.

5. Summary Table: Pain Fibers, Ganglia, and Neurotransmitters

Feature	Fiber Type	Conduction	Pre/Post-ganglionic?	Neurotransmitters
Sharp pain	A-delta	Fast	Sensory (DRG)	Glutamate
Dull pain	C fiber	Slow	Sensory (DRG)	Glutamate, Substance P
Sympathetic modulation	Preganglionic	Myelinated	Preganglionic → Ganglion	Acetylcholine
Sympathetic modulation	Postganglionic	Unmyelinated	Ganglion → target	Norepinephrine
Descending inhibition	CNS interneurons	N/A	N/A	GABA, Glycine, 5-HT, NE, Endorphins

6. Key Points

• Pain transmission is multi-step: peripheral nociceptors → spinal cord → thalamus → cortex.

• Fiber type determines speed and quality of pain.

• Neurotransmitters vary: excitatory (glutamate, Substance P, CGRP) vs inhibitory/modulatory (GABA, glycine, opioids).

• Sympathetic system modulates visceral pain.

• Descending pathways can suppress or amplify pain.

Oxycodone is an opioid analgesic, and its effects, including constipation, are directly related to mu (μ) opioid receptor activation.

1. Mechanism: Why Oxycodone Causes Constipation

A. Mu Receptors in the GI Tract

• Location: Mu receptors are found throughout the central nervous system and peripheral tissues, including:

  1. Brain – thalamus, cortex, brainstem → analgesia, euphoria, respiratory depression

  2. Spinal cord – dorsal horn → inhibit pain transmission

  3. GI tract – enteric nervous system, especially:

     • Myenteric plexus (Auerbach’s) – controls motility

     • Submucosal plexus (Meissner’s) – controls secretion

  4. Other tissues – urinary tract, cardiovascular, immune cells

B. Effect on GI System

1. Decreased motility

   • Mu receptor activation in the myenteric plexus inhibits smooth muscle contraction → slower peristalsis.

2. Increased sphincter tone

   • Anal sphincter tightens → harder stool passage.

3. Reduced intestinal secretion

   • Mu receptor activation decreases water and electrolyte secretion → drier stool.

Result: Opioid-induced constipation (OIC) – very common with chronic opioid therapy.

2. Other Mu-Receptor-Mediated Effects

System	Effect of Mu Activation
CNS	Analgesia, sedation, euphoria, respiratory depression
GI	Decreased motility, increased sphincter tone → constipation, nausea
Cardiovascular	Mild hypotension/bradycardia (central)
Urinary	Increased sphincter tone → urinary retention
Immune	Mild immunosuppression

3. Clinical Considerations for Patients on Oxycodone

1. Constipation prevention

   • Encourage high-fiber diet, hydration

   • Stool softeners (e.g., docusate)

   • Osmotic laxatives (e.g., polyethylene glycol)

   • Peripherally-acting mu-opioid receptor antagonists (PAMORAs) for severe OIC (e.g., methylnaltrexone)

2. Monitor for CNS effects

   • Sedation, confusion

   • Respiratory depression → especially in opioid-naïve or elderly patients

3. Other side effects

   • Nausea/vomiting

   • Urinary retention

   • Hypotension, especially postural

   • Risk of dependence/tolerance

4. Special populations

   • Elderly → more sensitive to constipation and sedation

   • Patients with renal or hepatic impairment → dosing adjustment required

4. Summary

• Oxycodone binds mu receptors in the CNS and GI tract.

• In the gut, mu receptor activation:

  • ↓ motility

  • ↑ sphincter tone

  • ↓ secretion
    → constipation

• Clinicians should monitor bowel function, hydration, CNS depression, and educate patients on preventive measures.