Editors' ChoicePain

New connections: Getting the good without the bad, opiate edition

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Sci. Signal.  21 Mar 2017:
Vol. 10, Issue 471, eaan2516
DOI: 10.1126/scisignal.aan2516

Researchers identify strategies to limit the adverse effects and liabilities of opioid receptor–targeting drugs.

Opioids are effective analgesics but are prone to abuse, which is associated with enormous health and social costs in the United States. In addition to their addiction potential, opioids that bind to the μ opioid receptor (MOR) have severe adverse effects in the CNS and intestinal tract. Strategies to mitigate the problems associated with the chronic use of MOR-targeting opioids are urgently needed. Reasoning that the acidosis that occurs in damaged tissue might result in MORs adopting a different conformation than that of MORs in undamaged brain or intestinal tissue, Spahn et al. designed a novel opioid that bound to MORs only at low pH. When tested in rodent models of inflammatory pain, this compound produced analgesia only in injured limbs without causing constipation, sedation, or addiction. Corder et al. (see also Puig and Gutstein) investigated the mechanisms underlying the development of tolerance, which necessitates ever increasing doses of opioids to achieve analgesic effects and which may paradoxically trigger opioid-induced hyperalgesia. They found that the development of these phenomena was prevented by selective genetic ablation of MORs from nociceptors, peripheral sensory neurons that transmit pain signals to the CNS, or by combining morphine with a MOR antagonist that was restricted to the periphery. Moreover, the combination of morphine and the peripheral MOR antagonist was effective at relieving various types of perioperative and chronic pain. In their investigation of mechanisms that contribute to opioid withdrawal symptoms, Burma et al. (see also Puig and Gutstein) focused not on neurons but rather microglia, the resident immune cells of the CNS. They found that opioid stimulation of microglia caused pannexin-1 (Panx-1) channels to release ATP, and that blocking Panx-1 with the antimalarial drug mefloquine or the gout medication probenecid reduced the severity of withdrawal symptoms in rodents. Similar to MOR-targeting opioids, those that target the κ opioid receptor (KOR) also have analgesic effects and can relieve intractable itch as well. Although they do not have the addiction potential of MOR-targeting opioids, they can cause dysphoria and sedation because they reduce dopamine release. Noting that KOR activation triggers multiple downstream signaling pathways, Brust et al. characterized a biased agonist of this receptor that preferentially activated one downstream pathway and that relieved itch in rodents without causing dysphoria or sedation. Together, these papers describe new approaches to pharmacologically target MORs, KORs, and other proteins without incurring the liabilities usually associated with opiates.

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