Pain Physiology

Nociception & Transduction - Ouch! It Starts Here

• Nociception: Neural encoding of noxious stimuli.
• Nociceptors: Free nerve endings detecting intense mechanical, thermal (>45°C, <5°C), or chemical stimuli.
  • Types: Mechanical, Thermal, Chemical, Polymodal, Silent (inflammation-activated).
  • Chemicals: Bradykinin, Prostaglandins, Histamine, Serotonin, H+, K+, ATP.
• Transduction: Noxious stimuli → action potentials via ion channels.
  • Key channels:
    • TRPV1 (heat >43°C, capsaicin, H+).
    • TRPM8 (cold, menthol).
    • TRPA1 (irritants, cold).
    • ASICs (acid).
    • Nav1.7 (Na+ channel).
• Peripheral Sensitization: ↑ Nociceptor responsiveness at injury.
  • Mediators: Prostaglandins (PGs), Bradykinin.
  • Results in hyperalgesia, allodynia.

⭐ TRPV1 receptor is activated by capsaicin, heat >43°C, and H+ ions (protons).

Pain Pathways - The Neural Superhighway

Pain signals ascend via a three-neuron chain:

• 1st Order Neuron (Primary Afferent):
  • Cell body: DRG (body); Trigeminal Ganglion (face).
  • Fibers: Aδ (fast, sharp, localized, myelinated); C (slow, dull, diffuse, unmyelinated).
  • Synapse: Dorsal horn (Rexed laminae I, II, V). NTs: Glutamate, Substance P.
• 2nd Order Neuron:
  • Location: Dorsal horn.
  • Decussates: Anterior white commissure.
  • Ascends in anterolateral system:
    • Spinothalamic tract (STT): To thalamus (pain, temp).
    • Spinoreticular tract: To reticular formation (arousal).
    • Spinomesencephalic tract: To PAG (modulation).
• 3rd Order Neuron:
  • Location: Thalamus (VPL-body, VPM-face). 📌 VPL for Lateral body/Legs; VPM for Medial face/Mouth.
  • Projects: Somatosensory cortex (S1, S2 - perception/localization); Limbic system (insula, cingulate - emotion).

⭐ The Spinothalamic tract is the principal pathway for transmitting nociceptive information to higher brain centers.

Pain Modulation - Turning Down the Volume

• Descending Inhibitory Pathways: Brain's natural analgesia.
  • Origin: Periaqueductal Gray (PAG), Rostral Ventromedial Medulla (RVM) including Nucleus Raphe Magnus (NRM), Locus Coeruleus (LC).
  • Neurotransmitters: Serotonin (5-HT from NRM), Norepinephrine (NE from LC), Enkephalins.
  • Action: Inhibit nociceptive transmission in dorsal horn (Substantia Gelatinosa).

• Gate Control Theory (Melzack & Wall):
  • Aβ fibers (touch) activate inhibitory interneurons in SG.
  • "Closes gate" to Aδ/C fiber pain signals.
  • Basis for TENS. 📌 Rubbing hurts less!
• Endogenous Opioids: (Enkephalins, Endorphins, Dynorphins)
  • Act on μ, δ, κ receptors.
  • Mechanism: ↓ $Ca^{2+}$ influx (pre-synaptic), ↑ $K^{+}$ efflux & hyperpolarization (post-synaptic).

⭐ Descending pathways primarily utilize serotonin and norepinephrine to inhibit pain signals at the spinal cord dorsal horn.

Pain Types & Clinical Links - Not All Aches Are Alike

• Nociceptive Pain: Normal response to tissue injury.
  • Somatic: Sharp, localized (skin, muscle, bone). E.g., fracture, burn.
  • Visceral: Dull, poorly localized, referred (organs). E.g., appendicitis, MI.
• Neuropathic Pain: Nerve damage/dysfunction (PNS/CNS).
  • Burning, tingling, shooting, "pins & needles".
  • E.g., diabetic neuropathy, post-herpetic neuralgia.
  • Features: Allodynia, hyperalgesia.
• Nociplastic Pain (Central Sensitization): Altered pain processing; no clear injury/neuropathy.
  • Widespread pain, fatigue. E.g., fibromyalgia, IBS.
• Referred Pain: Pain felt distant from origin.
  • Mechanism: Afferents converge on same spinal segment.

  ⭐ Kehr's sign: Spleen rupture (phrenic nerve C3-C5 irritation) causes left shoulder tip pain.

High‑Yield Points - ⚡ Biggest Takeaways

• Aδ fibers: fast, sharp pain (first pain); C fibers: slow, dull pain (second pain).
• Spinothalamic tract: primary ascending pathway for pain & temperature.
• Gate control theory: pain modulation in substantia gelatinosa of spinal cord.
• Endogenous opioids (endorphins, enkephalins) are natural analgesics.
• Referred pain: visceral pain felt at a distant somatic site.
• Neuropathic pain: due to nerve damage; often chronic and burning.
• Allodynia: pain from non-painful stimuli; Hyperalgesia: increased pain sensitivity.