Central Sensitization

As mentioned, peripheral injury of primary afferent sensory neurons can be associated with peripheral sensitization. Also, recruitment of previously silent nociceptive neurons can occur which remain active after the injury heals. The increase in nociceptive information arriving at the spinal cord from these peripheral sites can enhance the excitability of dorsal horn neurons,

Sympathetic Mast cell

Sympathetic Mast cell

Central Sensitization

Figure 1 (See color insert) The potential receptor mechanisms mediating depolarization and sensitization of visceral afferent neurons. Inflammatory mediators can be released from a variety of cell types present around the afferent nerve terminal such as mast cells, sympathetic varicosities, and blood vessels. Adenosine, histamine, and tryptase bind to G protein-coupled receptors while serotonin (5-HT), ATP, and capsaicin can activate NSCCs. This leads to a Ca2+ dependent modulation of ion channel activity. Second messenger systems such as cAMP couple the signals from these receptors to alterations in cellular function, thus mediating sensitization. Adenosine and PGE2 can generate cAMP directly via G protein-coupled stimulation of AC. Histamine however may act indirectly through generation of prostaglandins. Abbreviations: COX, cyclooxygenase; DAG, diacylglycerol; IP3, inositol triphosphate; PARs, protease-activated receptors; PLC, phospholipase C; PLA2, phospholipase A2; PKC, protein kinase C; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; NSCCs, nonselective cation channels; AC, adenyl cyclase; PGE2, prostaglandin E2; 5-HT, 5-hydroxytryptamine. Source: Adapted from Ref. 14.

Figure 1 (See color insert) The potential receptor mechanisms mediating depolarization and sensitization of visceral afferent neurons. Inflammatory mediators can be released from a variety of cell types present around the afferent nerve terminal such as mast cells, sympathetic varicosities, and blood vessels. Adenosine, histamine, and tryptase bind to G protein-coupled receptors while serotonin (5-HT), ATP, and capsaicin can activate NSCCs. This leads to a Ca2+ dependent modulation of ion channel activity. Second messenger systems such as cAMP couple the signals from these receptors to alterations in cellular function, thus mediating sensitization. Adenosine and PGE2 can generate cAMP directly via G protein-coupled stimulation of AC. Histamine however may act indirectly through generation of prostaglandins. Abbreviations: COX, cyclooxygenase; DAG, diacylglycerol; IP3, inositol triphosphate; PARs, protease-activated receptors; PLC, phospholipase C; PLA2, phospholipase A2; PKC, protein kinase C; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; NSCCs, nonselective cation channels; AC, adenyl cyclase; PGE2, prostaglandin E2; 5-HT, 5-hydroxytryptamine. Source: Adapted from Ref. 14.

through a variety of integrated mechanisms (Fig. 2). The central terminals of primary afferent neurons release a number of neurotransmitters including glutamate, substance P, prostaglandin E2 (PGE2), and brain-derived neurotrophic factor (BDNF). Increased levels of glutamate due to peripheral sensitization result in a removal of the magnesium ion block of the N-methyl-D-aspartate (NMDA) receptor and its subsequent activation (19). Glutamate also binds to ionotropic amino-methylene-phosphonic acid (AMPA) receptors and metabotropic glutamate receptors. Substance P binds to NK1 receptors, BDNF to tyrosine kinase B receptors, and PGE2 to endogenous prostanoid receptors on the postsynaptic membrane. A rise in intracellular postsynaptic calcium (Ca2+) levels triggers the activation of second messenger systems including cAMP, protein kinases A and C, and Ca2+-calmodulin-dependent protein kinase II (20). These kinases as well as tyrosine kinase Src phosphorylate AMPA and NMDA receptors, resulting in a further potentiation in their activity. The further release of nitric oxide and arachidonic acid (from cyclooxygenase-2 induction) potentiate presynaptic glutamate and prostaglandin release, respectively, thereby driving the cascade forward by a positive feedback loop.

This phenomenon has been termed "central sensitization'' and is believed to be responsible for the pain hypersensitivity that occurs in surrounding healthy tissues (secondary hyperalge-sia, or allodynia). Central sensitization is characterized by a decrease in threshold and an increase in response duration and magnitude to noxious stimuli and an expansion of the mechanosensitive receptive field of dorsal horn neurons (22). Both peripheral sensitization and central sensitization are the major mechanism in the development of neuropathic pain.

In animal models of cutaneous hypersensitivity, alterations in dorsal horn neuronal activity can be produced by peripheral tissue injury. Indeed, Jinks et al. demonstrated in anesthetized rats an expansion of the mechanical receptive field area of dorsal horn neurons after intracutaneous microinjection of histamine. Histamine evoked a dose-related increase in firing

Central Sensitization

Figure 2 The potential receptor mechanisms underlying the development of central sensitization. Peripheral sensitization results in an increased afferent barrage to neurons in the spinal dorsal horn. A number of neurotransmitters and mediators are released from the central terminals of primary afferents, which upregulate neuronal activity in postsynaptic neurons and facilitate transmission of the nociceptive information. Abbreviations: PGE2, prostaglandin E2; BDNF, brain-derived neurotrophic factor; NK1, neurokinin 1; MGR, metabotropic glutamate receptor; AA, arachidonic acid; COX-2, cyclooxygenase-2; AMPA, amino-methylene-phosphonic acid; NMDA, N-methyl-D-aspartate; EP, endogenous prostanoid; TrkB, tyrosine kinase B; PKA, protein kinase A; PKC, protein kinase C; PG, prostaglandin; CAMKII, Ca2+-calmodulin-dependent protein kinase II; PLC, phospholipase C. Source: Adapted from Ref. 21.

Figure 2 The potential receptor mechanisms underlying the development of central sensitization. Peripheral sensitization results in an increased afferent barrage to neurons in the spinal dorsal horn. A number of neurotransmitters and mediators are released from the central terminals of primary afferents, which upregulate neuronal activity in postsynaptic neurons and facilitate transmission of the nociceptive information. Abbreviations: PGE2, prostaglandin E2; BDNF, brain-derived neurotrophic factor; NK1, neurokinin 1; MGR, metabotropic glutamate receptor; AA, arachidonic acid; COX-2, cyclooxygenase-2; AMPA, amino-methylene-phosphonic acid; NMDA, N-methyl-D-aspartate; EP, endogenous prostanoid; TrkB, tyrosine kinase B; PKA, protein kinase A; PKC, protein kinase C; PG, prostaglandin; CAMKII, Ca2+-calmodulin-dependent protein kinase II; PLC, phospholipase C. Source: Adapted from Ref. 21.

rate as well as a dose-dependent expansion in mean receptive field area of dorsal horn neurons that was prevented by NMDA receptor antagonists (23). A number of animal studies have highlighted the important role of the NMDA receptor in mediating central sensitization and behavioral hyperalgesia after peripheral tissue inflammation/injury (24,25). Human studies have also confirmed the role of the NMDA receptor in mediating central sensitization, and its prevention and attenuation by NMDA receptor antagonism have been demonstrated not only in somatic tissues but also in the viscera (26-30).

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