The Neurobiology of Pain
What is Pain?
• Pain is part of the body's defense system.
• The reflex reaction to escape painful stimulus is meant to adjust behavior to avoid the harmful situation in the future.
Sensation & Perception of Pain
• The sensation of pain consists of four distinct processes:
»Transduction»Transmission» Interpretation »Modulation
Transduction
• Nociceptors are stimulated in skin and muscle.• Noxious stimulus affects a periphery sensory
nerve ending.• Neuron is depolarized.• Electrical impulse is generated
Transmission
• Impulse is transmitted or carried throughout the nervous system.
• Spinothalamic tract is the most important pathway for transmission.
»We will come back to this
Interpretation • Subjective interpretation of pain.• How does it feel?– Sharp, Dull, Ache, Burn, etc.
• Behavioral, psychological, and emotional factors involved.
Modulation
• Modulation can either suppress or aggravate pain.
• Neural response.• Peptides, amino acids, neurotransmitters and
other mediators are released.• Chemical messages are released.
Transduction
Nociception
• Sensory neurons, called nociceptors, are found in every part of the body that can sense pain.– Skin, muscle, joints, and the digestive tract.
• When exposed to noxious stimuli, an action potential is generated and driven from the periphery toward the CNS
• There are four main categories of nociceptors: Thermal, Chemical, Mechanical and Sleeping.
Types of Nociceptors
• Thermal Nociceptors:– Detect hot or cold noxious stimuli.
• Mechanical Nociceptors:– Detect noxious pressure or deformation, such an an
incision.• Chemical Nociceptors:– Respond to many different types of chemicals, including
capsaicin.• Sleeping / Silent Nociceptors:– Only respond to post-injury inflammation.
Types of Nociceptive Pain
• Superficial Somatic pain is caused by injury to the skin or superficial tissues– produces a sharp, localized pain of short duration.
• Deep Somatic pain originates from ligaments, tendons, bones, and muscles.– Produces a dull, aching, non-localized pain of longer
duration. • Visceral pain originates from the body’s organs.– Produces more of an aching or cramping pain that is of a
longer duration than somatic pain
Pain Pathway
Transmission
• Activation nociceptors by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord.– How?
Peripheral Nerves
• Nerves can either be slow or fast.– The slower type neural fibers are
deeper in the skin and transmit signals at a rate of 1-2 meters per second on un-myelinated C neurons.
– The fast type pain sensors require an intense stimulus to activate and transfer signals that are perceived as acute sharp stinging pain at a rate of 5 to 30 meters per second along myelinated A Delta neurons
The Spinal Cord• The signal reaches the Dorsal Horn of the spinal cord.• Action potentials induce neurotransmitter release.
– Voltage gated sodium ion channels – Glutamate (fast) binds to ionotropic AMPA and NMDA receptors.
The Brain
• From the dorsal horn, the signals are carried along the Spinothalamic Tract to the Thalamus, Cortex, PAG and other regions of the brain.
The Descending Pain Pathway
• The descending pathway of the spinal processing of nociceptive input is relayed through the:
»Periaqueductal gray»Frontal Cortex» Insula»Amygdala»Hypothalamus»Brainstem
Other Types of Pain
• Inflammatory pain– This type of pain results from the cascade of
biochemical events that are initiated with tissue damage.
• Neuropathic pain– Pain generated independently by the nervous system
resulting directly from action on nerves, such as severing. May also result from the culmination of physiological processes that are set in motion by persistent nociceptive or inflammatory processes.
Inflammatory / Neuropathic Pain
Treatment
NSAID’s
• Non Steroid Anti Inflammatory Drugs– The most prominent members of this group of drugs are
aspirin, ibuprofen, and naproxen.• They act as non-selective inhibitors of the enzyme
cyclooxygenase.– Inhibition of COX-1 and COX-2
• Cyclooxygenase catalyzes the formation of prostaglandins.– Prostaglandins act as messenger molecules in the
process of inflammation
Cox-2 Inhibitors
• A form of NSAID that directly targets COX-2.– i.e., Celebrex and Vioxx
• Similar in effectiveness to NSAID’s, but do not cause the gastrointestinal problems common to non-specific COX inhibitors.
• May increase the risk for heart attack and stroke
Opioids
• Opioids are commonly prescribed for moderate to severe pain.– Morphine, Vicodin, OxyContin, etc.
• They work by blocking the transmission of pain signals to the brain.
• Many side effects – Addiction, tolerance, risk for overdose, respiratory
depression.• We will explore this class of drugs in depth next
lecture.
Off – Label Perscriptions
• Some medications typically prescribed for other non-pain conditions can be used for pain relief of certain conditions.– Axiolytics (Benzodiazepines)– Antidepressants (SSRI / Tricyclic)– Anticonvulsants – Muscle Relaxers
Nociceptor
Peripheral Nerve
Interneuron
AscendingPathway
Descending Pathway
Sympathetic Efferent's
Spinal Cord
NSAID’sOpioids
Opioids
Opioids
Tricyclics
Antidepressants
AnxiolyticsAnticonvulsants
Alpha-1 BlockersAlpha-2 Agonists
NMDA Receptor Blockers