This occurs by a spread of the change in synaptic strength from activated to neighboring non-activated synapses, as opposed to changes in LTP which are usually restricted to a single dendritic spine coactivated by two inputs. Heterosynaptic facilitation after brief nociceptor triggering input can last for hours while homosynaptic LTP may last longer. Mechanistically, central sensitization includes pre- and postsynaptic changes as well as an increase in post synaptic membrane excitability (Latremoliere and Woolf, 2009). As for LTP, alterations in postsynaptic calcium levels are a major

driver in initiating change in synaptic strength: Calcium change can be caused by calcium flux through ionotropic receptors and voltage-gated calcium channels or by release from intracellular stores on activation of metabotropic receptors or receptor tyrosine kinases (Cheng et al., 2010 and Ohnami et al., Ku0059436 2011). Cav1.2 L-type see more calcium channels play important roles and can undergo bidirectional regulation by miR-103 to initiate some forms of central sensitization (Favereaux et al., 2011 and Fossat et al., 2010). Calcium-dependent intracellular signaling pathways produce posttranslational and transcriptional changes in many effector proteins, altering their levels,

distribution, and functional activity (Asiedu et al., 2011, Katano et al., 2011, Matsumura et al., 2010 and Miletic et al., 2011). The major players in the synaptic changes underlying activity-dependent central sensitization are the NMDA, AMPA, and mGluR glutamate receptors, the substance P NK1 receptor, BDNF and its TrkB receptor, ephrinB and EphBR, CaMKII, PKA, PKC, src, ERK and CREB,

and Kv4.2 (D’Mello et al., 2011, Hu and Gereau, 2011, Latremoliere and Woolf, 2009 and Nozaki et al., 2011). Central sensitization in normal individuals can only be initiated by a conditioning nociceptor input, because these afferents corelease glutamate and neuropeptides, mafosfamide providing greater opportunity for sufficient postsynaptic calcium increase. After nerve injury, however, Aβ fibers can undergo phenotypic changes including increased expression of neuropeptides (Nitzan-Luques et al., 2011) such that they may acquire the capacity to trigger or maintain central sensitization (Figure 4). More recently, changes in dendritic spines in dorsal horn neurons mediated by the monomeric G protein Rac1 have been detected after peripheral nerve injury, indicating that spinal circuitry may physically change after nerve injury (Tan et al., 2011). In addition, it appears that some individuals have a higher susceptibility, due to genotypic differences, in producing central sensitization, and therefore have a higher risk of neuropathic pain development or persistence (Campbell et al., 2009, Tegeder et al., 2006 and Tegeder et al., 2008).