Figure 9. Different mechanisms of pain and possible treatments: C fibers are modulated by sympathetic input with spontaneous firing of different neurotransmitters to the dorsal root ganglia, spinal cord and cerebral cortex. Sympathetic blockers (e.g. clonidine) and depletion of axonal substance P used by C fibers as their neurotransmitter (e.g. by capsaicin) may improve pain. In contrast Aδ fibers utilize Na+ channels for their conduction and agents that inhibit Na+ exchange such as antiepileptic drugs, tricyclic antidepressants, and insulin may ameliorate this form of pain. Anticonvulsants (carbamazepine, gabapentin, pregabalin, topiramate) potentiate activity of g-aminobutyric acid and inhibit Na+ and Ca2+ channels, N-methyl-D-aspartate receptors, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. Dextromethorphan blocks N-methyl-D-aspartate receptors in the spinal cord. Tricyclic antidepressants, selective serotonin reuptake inhibitors (e.g. fluoxetine), and serotonin and norepinephrine reuptake inhibitors inhibit serotonin and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems in the brain. Tramadol is a central opioid analgesic. α2 antag, α 2 antagonists; 5HT, 5-hydroxytryptamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DRG, dorsal root ganglia; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartate; SNRIs, serotonin and norepinephrine reuptake inhibitors; SP, substance P; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; modified from Vinik et al. 27