Central Nervous System Neurotransmitters, Receptors, and Drug Targets

DISINHIBITION

Several local inhibitory circuits and descending inhibitory pathways serve to modulate the perception of pain. However, after peripheral nerve injury, primary afferents, dorsal horn neurons, and gamma-aminobutyric acid (GABA)ergic inhibitory neurons undergo a number of maladaptive changes. Primary afferents express fewer opioid receptors, and dorsal horn neurons are less susceptible to inhibition by mu opioid agonists. Activation of GABAergic receptors may provoke paradoxic excitation and spontaneous activity. This loss of local inhibition promotes pain transmission, especially the Aβ-fiber–mediated pain.

LOW-THRESHOLD Aβ-FIBER–MEDIATED PAIN

These fibers mediate not only touch, pressure, vibratory, and joint movement sensation but also, and very importantly, the suppression of nociceptive pain caused by rubbing the affected area. However, after neural lesions, Aβ fibers begin to activate superficial dorsal horn nociceptive projection neurons. Peripheral injury induces regenerative responses to help damaged neurons in reconnecting with their targets. These gene-activated growth stimuli may cause sprouting of Aβ fibers into the superficial layers of dorsal horn. Regenerative sprouts may demonstrate ectopic activity or be activated by otherwise subthreshold stimuli. Along with central sensitization, these changes manifest clinically as the ability to generate pain in areas outside of injured nerve territories, and is usually coupled with a loss of C-fiber terminals.

NEUROIMMUNE INTERACTIONS

Macrophages have a central role in the immune surveillance of the peripheral nervous system. They clear cellular debris and serve as antigen-presenting cells to activate T lymphocytes. Both macrophages and T cells use cytokines and chemokines as means of communication with neurons, oligodendrocytes, Schwann cells, and spinal microglia. Peripheral nerve injury unleashes microglial activation in the dorsal horn; this occurs in close proximity to the injured afferent. The activated spinal microglia express chemokine receptors and release immune mediators (interleukin [IL]-1B, IL-6, tumor necrosis factor-alpha [TNF-alpha], BDNF), inducing and maintaining maladaptive pain conditions. Mediators released by microglia and astrocytes, as well as cytokines/chemokines produced by DRG cells directly activate nociceptors, cause peripheral sensitization by increasing the excitability of primary afferents, and stimulate adjacent chemokine-expressing neurons. Changes in the expression and function of the transient receptor potential channels and increases in sodium and calcium currents contribute to induction of action potentials. TNF-alpha also has been shown to stimulate DRG neurons and enhance the expression of chemokines, and its antagonists abolish neuropathic pain behavior in animal models.

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