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

There are multiple types of nociceptors:
they can be classified by sensory modality, conduction velocity, sensitivity to growth factors, peptide expression, site of termination in the dorsal horn

Nociceptor-specific Na+ channels

Afferent fiber conduction and pain

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

Two populations of nociceptors project to different sub-regions of the superficial dorsal horn

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.

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

-projection neurons
-excitatory interneurons
-inhibitory interneurons

Synaptic transmission in the dorsal horn

Nociceptors synapse with dorsal horn neurons in lamina I, II, and V

Nociceptors and local excitatory interneurons release glutamate as the fast transmitter, some also release co-transmitters such as peptides with slower excitatory action

Local inhibitory interneurons release GABA and glycine as fast transmitters, some also release co-transmitters.

Descending inputs synapse with projection neurons, interneurons, and terminals of the nociceptors

Glutamate receptor families

Synaptic transmission between nociceptors and dorsal horn neurons

Sensitization in the pain pathway may result in hyperalgesia (hypersensitivity to a noxious stimulus) and allodynia (pain that results from a non-noxious stimulus).

- Peripheral sensitization
skin and viscera
- Central sensitization
dorsal horn
higher centers

Thermal injury can cause hyperalgesia

Peripheral terminals of primary afferent nociceptors respond to inflammatory mediators

Central sensitization is sometimes due to neural plasticity in the spinal cord dorsal horn:

- Activation of nociceptive dorsal horn neurons
- Modulation producing long lasting central sensitization

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

Modulation of neural plasticity in the spinal cord dorsal horn: altered connectivity and cell death

Prostanoids and central sensitization

Ascending nociceptive pathway

Descending pathway that regulates nociceptive signaling in dorsal horn

Descending brainstem connections for pain modulation: on and off cells

Opioids are important regulators of nociceptive signaling and they act at many levels of the nervous system:
- primary afferents
- dorsal horn neurons
- higher centers

Opioid receptors – 3 gene families

Opioid receptor action

Local circuit interneurons

Summary:


	Nociceptors synapse with dorsal horn neurons in lamina I, II, and V

	Nociceptors and local excitatory interneurons release glutamate as the fast transmitter, some also release co-transmitters such as peptides with slower excitatory action

	Local inhibitory interneurons release GABA and glycine as fast transmitters, some also release co-transmitters.

	Descending inputs synapse with projection neurons, interneurons, and terminals of the nociceptors