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A sensitization of pain\u2010related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro\u2010adaptive changes occur as a consequence of excessive opioid exposure, including a recruitment of corticotropin\u2010releasing factor (<jats:styled-content style=\"fixed-case\">CRF<\/jats:styled-content>) and norepinephrine (<jats:styled-content style=\"fixed-case\">NE<\/jats:styled-content>) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on hyperalgesia\u2010like behavior during heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self\u2010administered heroin produced a significant mechanical hypersensitivity. During acute opioid dependence, systemic administration of the<jats:styled-content style=\"fixed-case\">CRF<\/jats:styled-content><jats:sub>1<\/jats:sub>receptor antagonist<jats:styled-content style=\"fixed-case\">MPZP<\/jats:styled-content>(20\u2009mg\/kg) alleviated withdrawal\u2010induced mechanical hypersensitivity. In contrast, several functional adrenergic system antagonists (clonidine, prazosin, propranolol) failed to alter mechanical hypersensitivity in this state. We then determined the effects of chronic<jats:styled-content style=\"fixed-case\">MPZP<\/jats:styled-content>or clonidine treatment on extended access heroin self\u2010administration and found that<jats:styled-content style=\"fixed-case\">MPZP<\/jats:styled-content>, but not clonidine, attenuated escalation of heroin intake, whereas both drugs alleviated chronic dependence\u2010associated hyperalgesia. These findings suggest that an early potentiation of<jats:styled-content style=\"fixed-case\">CRF<\/jats:styled-content>signaling occurs following opioid exposure that begins to drive both opioid\u2010induced hyperalgesia and eventually intake escalation.<\/jats:p>","DOI":"10.1111\/adb.12120","type":"journal-article","created":{"date-parts":[[2013,12,13]],"date-time":"2013-12-13T12:06:13Z","timestamp":1386936373000},"page":"275-284","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Chronic<scp>CRF<\/scp><sub>1<\/sub>receptor blockade reduces heroin intake escalation and dependence\u2010induced hyperalgesia"],"prefix":"10.1111","volume":"20","author":[{"given":"Paula E.","family":"Park","sequence":"first","affiliation":[{"name":"Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla CA USA"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences University of California 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