pain and temperature

Nociception

Detection and neural processing of potentially tissue-damaging stimuli. Does not necessarily produce conscious pain

Pain

An unpleasant sensory and emotional experience. Can occur without ongoing tissue damage or nociceptor activity

Nociceptors

Primary sensory neurons that detect potentially harmful mechanical, thermal, or chemical stimuli

Aβ fibers

Large, heavily myelinated fibers that primarily detect innocuous touch and conduct rapidly at approximately 16–100 m/s

Aδ fibers

Small, thinly myelinated fibers that transmit fast, sharp, relatively localized pain at approximately 5–30 m/s

C fibers

Small, unmyelinated fibers that transmit slow, burning, aching pain, temperature, and itch at approximately 0.5–2 m/s

First pain

Fast, sharp, well-localized pain primarily transmitted by Aδ fibers

Second pain

Slow, burning, aching, diffuse pain primarily transmitted by C fibers

Why does pain occur in two waves?

A single noxious stimulus activates both Aδ and C fibers, but Aδ fibers conduct faster and arrive first

Sensory transduction

Conversion of a physical or chemical stimulus into a change in membrane potential

Receptor potential

A graded change in membrane potential produced when sensory transduction channels open

TRPV1

A cation channel activated by noxious heat around 43°C or above and capsaicin

TRPM8

A cation channel activated by cooling and menthol that produces cold sensation

How does TRPV1 activation produce pain?

TRPV1 opens, Na⁺ and Ca²⁺ enter the nociceptor, the membrane depolarizes, and action potentials can be generated

Why does capsaicin feel hot?

Capsaicin activates TRPV1 channels, stimulating the same sensory neurons activated by noxious heat even without an increase in temperature

Why does menthol feel cold?

Menthol activates TRPM8 channels on cold-sensitive sensory neurons, producing a cooling sensation without necessarily lowering tissue temperature

How does a receptor potential become an action potential?

Transduction channels open → cations enter → graded depolarization → threshold reached → voltage-gated Na⁺ channels open → action potential

Nav1.7

A voltage-gated Na⁺ channel that helps regulate nociceptor excitability and is encoded by SCN9A

Loss-of-function Nav1.7 mutation

Can cause congenital insensitivity to pain because nociceptors have difficulty generating normal action potentials

Gain-of-function Nav1.7 mutation

Can cause severe pain syndromes because nociceptors become excessively excitable

Where are nociceptor cell bodies located?

Dorsal root ganglia or trigeminal ganglia

Where do nociceptor central axons enter the spinal cord?

Through the dorsal roots

Dorsal horn

The spinal cord region where nociceptive afferents synapse with interneurons and projection neurons

How does glutamate transmit pain signals in the dorsal horn?

Nociceptor action potentials cause presynaptic Ca²⁺ entry → vesicle fusion → glutamate release → AMPA receptor activation → fast EPSP

AMPA receptors

Ionotropic glutamate receptors that produce rapid excitatory postsynaptic potentials in dorsal horn neurons

NMDA receptors

Glutamate receptors that require glutamate and sufficient postsynaptic depolarization to conduct current, allowing Ca²⁺ entry

Why is the NMDA receptor Mg²⁺ block important?

At resting potential Mg²⁺ blocks the pore. Depolarization removes the block, allowing NMDA-mediated Ca²⁺ influx

Substance P

A neuropeptide released by nociceptors that activates NK1 GPCRs and produces slower excitatory effects

Fast versus slow pain synaptic signaling

Glutamate activates ionotropic receptors for fast excitation, while substance P activates NK1 GPCRs for slower signaling

Anterolateral system

The major ascending pathway carrying pain and temperature information. Projection neurons cross within the spinal cord

Dorsal column-medial lemniscal pathway

The major ascending pathway for fine touch. Fibers cross in the medulla

Peripheral sensitization

Increased sensitivity of peripheral nociceptors caused by inflammatory mediators modifying receptor and ion-channel function

Inflammatory soup

Chemical signals released by damaged and immune cells that activate receptors on nociceptor endings and increase excitability

How do inflammatory mediators increase nociceptor sensitivity?

Inflammatory mediators bind receptors → intracellular kinase pathways activate → kinases phosphorylate ion channels → channels become easier to activate → greater depolarization

Prostaglandin sensitization pathway

Prostaglandin binds Gs-coupled receptor → adenylyl cyclase produces cAMP → PKA activates → ion channels are phosphorylated → nociceptor sensitivity increases

How does ibuprofen reduce inflammatory pain?

Ibuprofen inhibits COX enzymes → less prostaglandin synthesis → less sensitizing GPCR signaling → reduced nociceptor excitability

Does ibuprofen directly block action potentials?

No. It reduces inflammatory mediator production and therefore decreases nociceptor sensitization

Central sensitization

Increased responsiveness of dorsal horn neurons following repeated nociceptor activity, allowing the same input to produce a larger response

Windup

Progressive increases in dorsal horn neuron firing during repeated nociceptive stimulation due to summation and NMDA receptor activation

How does repeated pain activate NMDA receptors?

Repeated glutamate release produces sustained depolarization → Mg²⁺ block is removed → Ca²⁺ enters through NMDA receptors → intracellular signaling increases excitability

Hyperalgesia

An exaggerated pain response to a stimulus that is already painful

Allodynia

Pain produced by a normally nonpainful stimulus, such as clothing lightly brushing the skin

KCC2

A transporter that helps maintain low intracellular Cl⁻ in neurons, allowing GABAergic and glycinergic inhibition to function normally

What happens when KCC2 function decreases?

Intracellular Cl⁻ regulation changes → GABA and glycine inhibition becomes less effective → dorsal horn neurons become more excitable

Gate control theory

Touch input from Aβ fibers activates inhibitory spinal interneurons, which suppress nociceptive transmission

How does rubbing an injury reduce pain?

Rubbing activates Aβ touch afferents → inhibitory interneurons activate → nociceptive signaling is suppressed in the dorsal horn

How can spinal inhibition reduce pain?

Inhibitory interneurons release GABA and glycine, decreasing projection-neuron excitability and/or reducing neurotransmitter release from nociceptor terminals

How can nerve injury cause mechanical allodynia?

Injury weakens inhibitory spinal circuits, allowing normally harmless Aβ touch signals to activate nociceptive projection neurons

How does histamine produce itch?

Mast cells release histamine → histamine binds H1 receptors on pruriceptors → intracellular signaling increases neuronal activity → action potentials transmit itch

Pruriceptors

Specialized sensory neurons that detect itch-inducing stimuli

GRP

Gastrin-releasing peptide signaling that contributes to itch transmission in the dorsal horn

Why does scratching temporarily relieve itch?

Scratching activates touch and nociceptive afferents that recruit inhibitory spinal circuits, suppressing itch transmission

Why can scratching worsen itch over time?

Repeated scratching damages skin and causes additional inflammation, creating an itch-scratch cycle

Descending pain modulation

Brainstem pathways regulate spinal nociceptive transmission and can either inhibit or facilitate pain signaling

PAG

Periaqueductal gray, a brain region involved in descending pain modulation

How do descending pathways alter pain?

Brainstem signals involving serotonin and noradrenaline modify dorsal horn neuron activity and nociceptive transmission

Endogenous opioids

Enkephalins, endorphins, and dynorphins that activate opioid receptors to suppress nociceptive signaling

μ-opioid receptor

A Gi/o-coupled GPCR activated by morphine and endogenous opioid peptides that reduces neuronal excitability

Presynaptic opioid inhibition

μ-opioid receptor activation reduces voltage-gated Ca²⁺ channel activity → less Ca²⁺ enters → less vesicle fusion → less glutamate release

Postsynaptic opioid inhibition

μ-opioid receptor activation increases GIRK K⁺ conductance → K⁺ exits → membrane hyperpolarizes or stabilizes → neuron becomes less likely to fire

How does morphine reduce pain?

Morphine activates μ-opioid receptors → inhibits presynaptic Ca²⁺ entry and increases postsynaptic K⁺ conductance → reduces nociceptive transmission

GIRK channels

G-protein-gated inwardly rectifying K⁺ channels that increase K⁺ conductance and help hyperpolarize postsynaptic neurons

Endocannabinoids

Lipid-derived signaling molecules that travel retrogradely from postsynaptic neurons to presynaptic CB1 receptors and suppress neurotransmitter release

Placebo analgesia

Reduction in pain perception through expectations and context, sometimes involving endogenous opioid signaling

Naloxone

An opioid receptor antagonist that can block certain endogenous opioid-mediated placebo analgesic effect