Multiple approaches have been performed to elucidate the molecular mechanisms underlying drug withdrawal in opioid-dependent animals. Opiate withdrawal represents a state of neuronal hyperexcitability in the brain that leads to alterations in a number of second-messenger systems which, in turn, induce expression of transcription factors. Whereas earlier studies have primarily demonstrated an early and transient transcriptional activation of members of the Fos, Jun, and Krox families, recent microarray studies investigating the delayed response could additionally identify several transcriptional repressors such as cAMP response element modulator (CREM), IkappaB, silencer factor B, helix-loop-helix proteins, or glucocorticoid-induced leucine zipper, indicating the attempt of the brain to re-establish homeostasis after withdrawal-induced excitation.
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