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One overall difficulty in interpretation of these in vivo studies is the fact that sometimes the ERK1/2 activation occurs in opioid-sensitive neurons and other times is indirect via disinhibition of other neurons or perhaps by activation of ERK1/2 signaling pathways in glia or astrocytes (Eitan et al., 2003

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Gradual dose escalation assists in identifying the minimum effective dose and reduces the risk of sudden adverse tissue reactions

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