Somatosensory Physiology: Receptors, Pain Pathways & Modulation

Transduction

Conversion of a stimulus's energy into a change in membrane potential

Receptor (generator) potential

Graded depolarization at the transduction site, proportional to stimulus strength (NOT all-or-none)

Larger receptor potential: effect on action potential SIZE

No effect (APs are all-or-none); AP FREQUENCY increases

Increased pressure on a Pacinian corpuscle: effect on AP frequency

Increases

Ion channel opened in a Pacinian corpuscle

Mechanically gated Na+ channels (membrane stretch); Na+ influx depolarizes

Pacinian corpuscle adaptation type

Phasic (rapidly adapting); fires at stimulus ON and again at OFF

Na+ channel blocker applied to a Pacinian corpuscle

No depolarization and no action potential

Labeled line

Stimulus type (modality) is coded by which receptor and pathway is active

How stimulus intensity is coded

Firing frequency (rate code) + number of receptors recruited (including higher-threshold ones)

Receptive field

Patch of receptor surface that, when stimulated, changes a neuron's firing

Larger receptive field: effect on localization

Decreases localization (small fields = fine localization/high acuity)

Sensitivity to touch: large vs small receptive field units

Small receptive field is greater (better acuity)

Lateral inhibition

Active neuron inhibits its neighbors via inhibitory interneurons; sharpens edges and INCREASES localization precision

Tonic receptor

Slowly adapting; fires throughout the stimulus; no off response; codes steady pressure/position/pain

Phasic receptor

Rapidly adapting; burst at onset (and an OFF response); codes change/vibration/movement

Which receptor type has an off response?

Phasic

Examples of tonic receptors

Merkel discs, Ruffini endings, muscle spindles (static), nociceptors

Examples of phasic receptors

Pacinian, Meissner corpuscles, hair follicle receptors

Touch (dorsal column-medial lemniscus) pathway

DRG afferent → same-side dorsal column → dorsal column nuclei (medulla; first synapse) → cross in medulla (medial lemniscus) → thalamus (VP) → S1

Where does the touch pathway cross?

In the medulla

Where does the pain pathway cross?

In the spinal cord (immediately after the dorsal horn synapse)

Primary somatosensory cortex (S1) location

Postcentral gyrus of the parietal lobe, just behind the central sulcus

Damage to parietal lobe directly behind central sulcus: effect on proprioception

Decreases

Postcentral vs precentral gyrus

Postcentral = S1 (feel); precentral = M1 (move); both contralateral

Sensory homunculus area is proportional to

Innervation density (not body size)

Genitals: space in sensory vs motor cortex

Sensory cortex gets much more space than motor cortex

Owl monkey digit 3 amputation result

Cortical territory is taken over by digits 2 and 4

Phantom limb: mirror box therapy mechanism

Visual illusion tricks the brain into thinking it is controlling the amputated limb

Barrel cortex

Rodent cortex in which each whisker has its own cortical barrel (one-to-one map)

Aα fibers (group I)

Fastest, heavily myelinated; proprioceptors (spindles, GTOs)

Aβ fibers (group II)

Myelinated; mechanoreceptors (touch)

Aδ fibers

Thin myelin; sharp, fast "first pain"; cold

C fibers

Unmyelinated, slowest; dull, burning, long-lasting "second pain"; temperature; itch

Nerve fiber speed order

Aα > Aβ > Aδ > C

Nociceptor ending type

Free nerve endings

TRPV1 (VR1)

Cation channel on nociceptors opened by heat (above ~43-45 °C), capsaicin, and protons; lets in Na+ and Ca2+

Inflammatory soup contents

K+, serotonin, prostaglandins, leukotrienes, bradykinin

Primary hyperalgesia

Peripheral sensitization of nociceptors at the injury site (lower thresholds)

Substance P at an injury site

Released from nociceptor terminals; mast cells release histamine, vessels dilate, swelling; INCREASES pain perception

Anterolateral (spinothalamic) pathway

Aδ/C → dorsal horn (same side; glutamate + substance P) → cross in cord → contralateral anterolateral system → thalamus → S1 + cingulate/insula; collaterals to PAG and reticular formation

Descending pain control

PAG (and amygdala) → rostroventral medulla (RVM) → dorsal horn interneurons release endogenous opioids that inhibit pain transmission

Endogenous opioids

Enkephalin, endorphin, endomorphin, dynorphin

Gate control of pain

Aβ touch fiber activity excites dorsal-horn inhibitory interneurons that close the gate on pain transmission

Where is pain's unpleasantness integrated?

Cingulate cortex (S1 = where/how intense)

Congenital insensitivity to pain

Loss-of-function mutation in the Nav1.7 sodium channel on nociceptors

Placebo analgesia

Partly opioid-based; blocked by naloxone

Accessory structures that limit sensory input

Eyelids, pupil constriction, stapedius and tensor tympani contraction

Heroin acts on

Opiate receptors

Cocaine acts on

Dopamine (receptors/system)

Benzodiazepines (e.g., Valium) act on

GABA receptors

Kim et al. 2009: primary vs secondary hyperalgesia location

Primary = at injection site (site P); secondary = surrounding uninjured skin (site S)

Secondary hyperalgesia mechanism

Central sensitization (hyperexcitable dorsal-horn pain-transmission neurons)

Kim 2009: what does EA affect?

REDUCES secondary hyperalgesia (central); NO effect on primary (peripheral)

Fig 1A labels I, X, P, S

I = capsaicin injection site; X = needle entry (heel); P and S = primary and secondary von Frey test sites

Capsaicin dose and route in Kim 2009

20 µg in 20 µl olive oil, intradermal, plantar LEFT hind paw of Sprague-Dawley rats

"Mechanical threshold" (y-axis)

50% paw-withdrawal threshold: von Frey filament stiffness at which the rat withdraws half the time

HIGH vs LOW mechanical threshold

High = stiff filament needed = LESS pain; low = withdraws to soft filament = MORE pain

Graph reading: NTX line lower than EA line

Rats respond to less stiff filaments = more pain (EA analgesia blocked)

EA parameters in Kim 2009

2 Hz, 3 mA, 30 min, starting 1.5 h after capsaicin (controls got anesthesia only)

Which acupoint pair worked in Kim 2009?

SI3-TE8 (forelimb); LI3-LI6 did nothing (control)

Ipsilateral vs contralateral SI3-TE8

Only ipsilateral worked (likely ipsilateral descending inhibition)

Phentolamine (PTL) effect on EA

None; adrenergic system is not necessary

Naltrexone (NTX) effect on EA

Blocked EA analgesia; mediator is the endogenous OPIOID system

Intrathecal NTX result

Almost completely blocked EA; opioid action is in the spinal cord

Spinal opioid receptor blockers in Kim 2009

CTAP (µ): almost complete block; naltrindole (δ): moderate block ~1 h; nBNI (κ): no effect

Low- vs high-frequency EA

2 Hz: endomorphin/enkephalin/endorphin, µ/δ, reduces SECONDARY hyperalgesia; 100 Hz: dynorphin, κ, reduces PRIMARY

Endogenous ligand to receptor matching

Endomorphin → µ; enkephalin → δ; dynorphin → κ; β-endorphin → µ and δ

Kim 2009 big conclusion

EA selectively inhibits centrally mediated pain by suppressing central sensitization through spinal µ and δ opioid receptors

Motor unit

A single motor axon and ALL the muscle fibers it innervates

Small vs large motor units

Small (fingers, eyes, lips) = fine control, more M1 space; large (thigh, back) = coarse control, less M1 space

Size principle

Small motor units are recruited first; force also graded by firing rate

NMJ sequence

AP → voltage-gated Ca2+ channels → Ca2+ in → ACh exocytosis (SNAREs) → nicotinic receptors → Na+ in (end-plate potential) → muscle AP → AChE breaks down ACh

Receptor at the neuromuscular junction

Nicotinic ACh receptor (ionotropic); muscarinic receptors are NOT at the end plate

Curare / nicotine effect on EPP

Curare (blocks nicotinic receptors) decreases EPP; nicotine (agonist) increases EPP

Myasthenia gravis

Autoantibodies destroy nicotinic ACh receptors; smaller EPPs, weaker contraction, less GTO firing; treat with acetylcholinesterase inhibitor

Tetanus toxin mechanism

Passed to presynaptic inhibitory interneurons; cleaves exocytosis proteins there; motor neurons disinhibited and release MORE ACh (spasms, exaggerated reflexes)

Muscle spindle

In muscle belly in PARALLEL with extrafusal fibers; intrafusal fibers; senses muscle LENGTH/rate of stretch; Ia (and II) afferents; γ motor neuron control

Golgi tendon organ (GTO)

In the tendon, in SERIES with muscle; senses TENSION/force; Ib afferent; inhibits same muscle to prevent overload

Role of γ motor neurons

Tighten intrafusal fibers so spindles stay sensitive during contraction

Stretch reflex (knee-jerk)

Tendon tap → spindle stretched → Ia afferent → monosynaptic excitation of quad α motor neuron → contraction; Ia also excites inhibitory interneuron to relax hamstring (reciprocal inhibition)

Effect of spindle activation

Increases contraction and decreases muscle length

Load-compensation loop

Added load stretches muscle → spindle afferent discharge increases → α motor neuron fires more → more force; negative feedback for length

Conscious vs unconscious proprioception pathways

Conscious: dorsal column-medial lemniscus → thalamus → S1; unconscious: spinocerebellar tracts to cerebellum

Motor hierarchy

M1 + non-primary motor cortex (premotor, SMA) → brainstem → spinal cord → muscles; basal ganglia and cerebellum modulate cortex via thalamus (no direct spinal projection)

Primary motor cortex location

Precentral gyrus, frontal lobe (layer V upper motor neurons)

Motor homunculus features

Contralateral; large hand/fingers/lips/tongue/face; little or no genital representation; plastic; directional tuning

Pyramidal pathway

M1 → internal capsule → cerebral peduncles → pyramids of medulla → ~85-90% cross in caudal medulla (lateral corticospinal tract) → α motor neurons in ventral horn → ventral root

Where does pyramidal decussation occur?

Medulla

Lower motor neuron / final common path

α motor neuron in the ventral horn; all influences on movement act through it

Mirror neurons

First recorded in area F5 of monkey ventral premotor cortex; fire when performing AND watching an action; proposed role in imitation

SMA vs premotor cortex

SMA = internally generated sequences, planning, mental rehearsal; premotor = movements guided by external/visual cues (contains F5)

Motor equivalence

Same act (e.g., signature) done with different muscles looks the same, so the motor plan is stored abstractly

Apraxia

Inability to perform skilled learned movements despite intact strength, sensation, understanding (planning problem, not paralysis)

Plegia vs paresis

Plegia = paralysis; paresis = weakness

Antagonist vs synergist muscles

Antagonists oppose each other (biceps/triceps); synergists pull in the same direction

Sliding-filament contraction

Ca2+ released from SR binds troponin → tropomyosin moves → myosin binds actin (power stroke, ATP) → thin filaments slide past thick → sarcomere shortens

Parkinson's disease

Death of dopaminergic neurons in the substantia nigra; hypokinetic: resting tremor, rigidity, slow movement, shuffling gait, masked face; treated with L-DOPA

Huntington's disease

Destruction of caudate and putamen; hyperkinetic: involuntary jerky movements (chorea); inherited dominant gene

Direct vs indirect basal ganglia pathway

Direct disinhibits thalamus and promotes intended movement; indirect suppresses competing programs

Cerebellar damage

Ataxia, intention tremor, past-pointing, decomposition of movement; IPSILATERAL side effects