Pain: Perception, Sensation, and Neural Pathways

Professor Arthur Butt

Structure of Lecture

1. Introduction
2. Pain: Perception and Sensation
3. The Pain Pathway
4. The Analgesic Ladder
5. Opioid Analgesics

Sensory system

Discussion Point: Nervous System Reactions to Pain

Discussion Point: Consider the following and explain the reactions of the nervous system to the sensations of pain.

Man gets out of a car. As he placed his foot down on a sharp object, he shrieked with pain and moved his foot up reflexively.

Consider the Following

• the concept of action potential and the negative charge on the inside of the membrane.
• how this electrical impulse is distinguished as painful, compared to, for example, normal pressure.
• the frequency and pattern of action potentials constitute a code for information transfer by neurons.

Sensory Receptors

• Sensory receptors
  • mechanoreceptors
  • thermoreceptors
  • chemoreceptors
  • Proprioceptors
  • nociceptors

Free nerve ending senses pain, itch, tickle, cold, or warmth.

Epidermis

Type I cutaneous mechanoreceptor (tactile disc) senses continuous touch and pressure.

Dermis

Corpuscle of touch (Meissner corpuscle) senses onset of touch and low-frequency vibrations.

Sensory neuron cell body 2

Subcutaneous layer

Type II cutaneous mechanoreceptor (Ruffini corpuscle) senses skin stretching and pressure.

Hair root plexus senses movements on skin surface that disturb hairs.

Lamellated (pacinian) corpuscle senses high- frequency vibrations.

• Transmit sensory information into the spinal cord and to sensory areas of the brain

To brain Spinal cord 3

Motor neuron cell body

Sensory neuron axon

Motor neuron axon

Pain: Perception & Sensation

• Pain = perception
  • subjective response
  • to a noxious stimulus

• Sensation = nociception
  • Nociceptors
  • free nerve endings

Message is receivedin the thalamusandcerebralcortex

Tissue-damaging stimulus activates nociceptors

Descendingpathway brain

Message carried to spinal cord

Different Kinds of Pain

• DIFFERENT KINDS OF PAIN:
  • Acute (physiological)
  • Inflammatory (pathological)
  • Neuropathic

Acute < 3 months Chronic > 3 months

Normal Inflammatory Neuropathic Nociceptive Pathophysiologic

Acute (Physiological) Pain

• Acute pain is a physiological response that warns us of danger.
• Nociception - normal processing of pain and the responses to noxious stimuli that are damaging or potentially damaging to normal tissue.

To brain Spinal cord 3

Motor neuron cell body

Sensory neuron cell body 2

Sensory neuron axon

Motor neuron axon

Inflammatory Pain

Inflammatory Pain

Tissue damage release of inflammatory mediators such as prostaglandins and bradykinin increase the sensitivity of nocipetors to noxious stimuli

Sensitization in the pain pathway hyperalgesia - hypersensitivity to a noxious stimulus (hypersensitive nociceptors) allodynia - pain that results from a non-noxious stimulus (low-threshold mechanoreceptors and thermoreceptors)

NSAIDs reduce production of prostaglandins

Mas cell

Substance P Histamine

Ventral

Promotes swelling

Dorsal root ganglion

Serotonin K+

Action potential

Prostaglandins Leukotrienes

Action potential

Dorsal

Spinal cord

Skin

Blood vessel

Substance P

Damaged cells release substances that excite nerve endings.

Action potentials can reflexively excite blood vessels and other cells to produce inflammation.

Information enters spinal cord.

Pain fibers release substance P and glutamate.

Neuropathic Pain

Peripheral neuropathic pain Postamputation pain (stump and phantom pain) Trigeminal neuralgia Painful radiculopathy Postherpetic neuralgia Painful polyneuropathy Peripheral nerve injury pain

Central neuropathic pain Central post-stroke pain

Neuropathic Pain is caused by damage or injury to the nociceptive nerves - peripherally or centrally.

The pain is usually described as a burning sensation and affected areas are often sensitive to the touch.

Spinal cord injury neuropathic pain (at- and below level pain)

Central pain in multiple sclerosis

Nociceptors

• Nociceptors are free nerve endings in the ski
• Many stimuli have been found to activate ion channels present on nociceptor terminals
• Act as molecular transducers to depolarize these neurons
• Thereby setting off nociceptive impulses along the pain pathway:
• Blocked by local anaesthetics, e.g. lidocaine

Nociceptors in Skin

Ventral

Epidermis

Free nerve endings

Dermis

Dorsal

Dorsal Spinal cord

root ganglion

Receptor activated

Peak ~+40

Membrane Voltage (mV)

0

Rising Phase Falling Phase

Threshold ~- 55

Failed Initiations

Resting Potential ~- 70

Undershoot

Stimulus

0 1 2 3 4 5 Time (ms)

TOvershoot!

• Na Na Na Na

Sodium channels OPEN

Na

TRPVI A A C N A

TRPV1 transient receptor potential cation channel vanilloid 1 (TRPV1) receptor - cation channel, activation results in sodium influx - activated by noxious heat, also low pH - leads to painful, burning sensation - sensitised by inflammatory agents

Clinical Significance of TRPV1 Antagonists

• Antagonists block TRPV1 activity, thus reducing pain
• TRPV1 antagonists have been developed - efficacy in reducing nociception from inflammatory and neuropathic pain models in rats
• In humans, major side-effect is hyperthermia restricted usefulness of these drugs

? N C No C

TRPV1 - noxious heat

TRPM8 (CMR1) - cold - TRP subfamily M member 8 (TRPM8) - cation channel - sodium influx in response to cold

Clinical Significance of TRPM8

• upregulated in patients with painful bladder syndrome
• may be a target in prostate cancer

ENaC/Degenerin family - mechanical stimuli - activated by mechanical stimuli

ASIC - acid sensing ion channel - belongs to the same family as ENaC - sodium channel activated by protons - acid

ASIC TRPM8 ENaC/DEG

Signal transductic nociceptors

CMRIASICS - Mamba Venom

Black mamba venom is 'better painkiller' than morphine

• Mamba venom is made up mostly of dendrotoxins (dendrotoxin-k, -1, - 3, and -7, among others)
• mambalgins - potent analgesic as strong as morphine - without most of the side-effects. - Block acid-sensing ion channels

a Venom

b C

Nter ASIC1a PH 5 Cter 200 nA Loop III 25 Å 60 s Loop Il Mambalgin-1

TTOGATO

Tech, Gadgets and Toys

Take two of these and call me in the morning.

Black mamba venom peptides target acid-sensing ion channels to abolish pain

Diochot et al. (2012) Nature

Students, explain your understanding of synapses. Discuss the direction of information flow between the presynaptic and postsynaptic neuron. At the end of the lecture. Is your understanding and knowledge of the process increased?

Loop |

The Pain Pathway

Frontal cortex

Cingulate cortex is especially activated by pain information.

Thalamic nuclei (e.g., ventral posterior, intralaminar, and parafascicular)

Forebrain

Pain information is distributed to many thalamic and cortical areas.

Periaqueductal gray

Midbrain

Reticular formation

Reticular formation

Brain stem sites control pain-related behavior such as vocalization.

Pons

Medulla

Pain information enters.

Anterolateral system: Neospinothalamic Paleospinothalamic

A8 and C fibers

Spinal cord

Perception of pain throughout the body arises when neural signals transmitted to specific higher order brain areas

• Cingulate Cortex mediates the emotional component of pain

SMA aMCC PAG

Descending Pain Control Circuit

Opiates decrease pain by modulating the descending pain pathway in a complex manner

SMA aMCC PAG

Opioids

Periaqueductal gray Nucleus raphe magnus Lateral tegmental nucleus

• Inhibitory synapse
• Excitatory synapse

Ad fiber

Serotonergic irenergic neuron

Enkephalin

S rgic neuron

E

Opioids

To spinothalamic tract

Pain Transmission in the Spinal Cord

Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord

Transmission

• for moderate pain axons release glutamate, with fast action
• stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions

To brain Spinal cord 3

Motor neuron sell body

Sensory neuron cell body VII VII 2

Com

Sensory neuron axon

Motor nairon ayon

Na+ Channel TTX sensitive

Na+ Channel TTX resistant

G: glutamate SP: substance P ATP

SP ATP

G G

Ca2+ voltage gated Ca2+ channel

Glutamate NMDA AMPA

Pain Transmission in the Spinal Cord - Second Order Neurons

Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord

Transmission

• for moderate pain axons release glutamate, with fast action
• stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions

Na+ Channel TTX sensitive

Na+ Channel TTX resistant

G: glutamate SP: substance P ATP

carbamazepine - NaCh

SP ATP

Ziconotide - conotoxin from cone snail

G G

Ca2+ voltage gated Ca2+ channel

Glutamate ketamine NMDA AMPA

Pain Transmission in the Spinal Cord - Inhibitory Interneurons

Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord

Transmission

• for moderate pain axons release glutamate, with fast action
• stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions

Local inhibitory interneurons release GABA and glycine

Na+ Channel TTX sensitive

Na+ Channel TTX resistant

G: glutamate SP: substance P ATP

SP ATP

GABA Gly

G G

Ca2+ voltage gated Ca2+ channel

gabapentin

Glutamate pregabalin NMDA AMPA

Pain Transmission in the Spinal Cord - Descending Control

Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord

Transmission

• for moderate pain axons release glutamate, with fast action
• stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions

Local inhibitory interneurons release GABA and glycine

Na+ Channel TTX sensitive

Na+ Channel TTX resistant

G: glutamate SP: substance P ATP

Descending pain control fibres release opioids to inhibit pain

SP ATP

GABA Gly

G G

Ca2+

Glutamate Encephalins NMDA AMPA

Descending Pain Control Circuit - Antidepressants

• Opiates decrease pain by modulating the descending pain pathway in a complex manner

Noradrenergic and Serotonergic Antidepressants - Tricyclics

• Treatment of neuropathic pain
• e.g. amitriptyline, doxepin, imipramine) inhibit reuptake of norepinephrine and serotonin

Periaqueductal gray Nucleus raphe magnus Lateral tegmental nucleus

• Inhibitory synapse
• Excitatory synapse

Ad fiber

Serotonergic renergic neuron

Enkephalin

S ergic neuron

E

To spinothalamic tract