Basic mechanisms of pain

To understand the pharmacology of pain, you must know the anatomy and physiology of the system.

1.   Peripheral nociceptors
2.   Dorsal horn – major center for integration of afferent and efferent signaling
3.   Ascending pathway
4.   Descending pathway

Different levels of pain processing and different sites for sensitization.

Different levels of pain processing and different sites for sensitization.

Different levels of pain processing and different sites for sensitization.

How are peripheral temperature and pain signals detected?

Signal transduction in nociceptors

Nociceptor-specific Na+ channels

Afferent fiber conduction and pain

Two populations of C and Ad fibers projecting to the superficial dorsal horn

Different levels of pain processing and different sites for sensitization.

Molecular mechanisms associated with peripheral sensitization

Peripheral terminals of primary afferent nociceptors respond to inflammatory mediators

The peripheral signal is carried to the spinal cord

Nociceptive inputs go to lamina I, II and V in the dorsal horn

Nociceptors terminating in the superficial dorsal horn release glutamate and peptides to excite dorsal horn neurons.

Synapses between primary afferent C fibers and dorsal horn neurons

Classes of neurotransmitter receptors

Glutamate receptor families

Synaptic transmission between nociceptors and dorsal horn neurons

Current-voltage relationship for synaptic currents mediated by AMPA and NMDA receptors

The spinal cord dorsal horn has a heterogeneous cell population including:


-projection neurons
-excitatory interneurons
-inhibitory interneurons

Dorsal horn neurons expressing receptor for substance P, the NK1 receptor.

Different levels of pain processing and different sites for sensitization.

Thermal injury can sensitize nociceptors

Activation of neural plasticity in the spinal cord dorsal horn: fast EPSPs

Central sensitization

Increased number of astrocytes in spinal cord in model of bone cancer

Increase in number of microglia following peripheral nerve injury accompanies tactile allodynia

Ascending nociceptive pathway- anterolateral white matter to the thalamus

Ascending Pain pathways:

-traditional
-lamina I

The thermal-grill illusion of pain
-burning pain with innocuous warm (40o) and cool (20o) bars.

Activation of the interoceptive or homeostatic cortex (the dorsal posterior insular cortex) by various modalities

Descending pathway that regulates nociceptive signaling in dorsal horn

Opioid receptors – 3 gene families

Opioid receptor action

Opioids are important regulators of nociceptive signaling

Local circuit interneurons

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