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The BBB supports CNS homeostasis via EC-associated transport of ions, nutrients, proteins and waste products between the brain and blood. These transport mechanisms also serve as physiological barriers to pathogens, toxins and xenobiotics to prevent them from contacting neural tissue. The mechanisms that govern BBB permeability pose a challenge to drug design for CNS disorders, including pain, but can be exploited to limit the effects of a drug to the periphery, as in the design of the peripherally acting \u03bc-opioid receptor antagonists (PAMORAs) used to treat opioid-induced constipation. Here, we describe BBB physiology, drug properties that affect BBB penetrance and how data from randomized clinical trials of PAMORAs improve our understanding of BBB permeability.<\/jats:p>","DOI":"10.1136\/rapm-2020-101403","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T01:54:43Z","timestamp":1595987683000},"page":"688-695","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Blood\u2013brain barrier: mechanisms governing permeability and interaction with peripherally acting \u03bc-opioid receptor antagonists"],"prefix":"10.1136","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-4396","authenticated-orcid":false,"given":"Eugene R","family":"Viscusi","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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