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...... 217 Peter F. McManus Charitable Trust to GWP. The authors declare no conflict of interest.

Michael H Baumann*,1 and Gavril W Pasternak2 1Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA; 2Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA Dr MH Baumann, Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Suite 4400, Baltimore, MD 21224, USA, Tel. +443 740 2660, Fax: +443 740 2241, E-mail: [email protected]

...... Frank RG, Pollack HA (2017). Addressing the Figure 1. Chemical structures of heroin, morphine, fentanyl, N-phenyl-N-[1-(2-phenylethyl)-4- fentanyl threat to public health. N Eng J Med 376: 605–607. piperidinyl]-2-furamide (furanylfentanyl) and 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N- Huang XP, Che T, Mangano T, Le Rouzic V, Pan YX, methylbenzamide (U-47700). Majumdar S et al Pharmacology of W-18 and W-15. Preprint at http://www.biorxiv.org/content/ early/2016/07/24/065623 (2016). Mohr AL, Friscia M, Papsun D, Kacinko SL, Buzby D, to which NSOs produce life-threaten- Although initially touted as a highly Logan BK (2016). Analysis of novel synthetic opioids U-47700, U-50488 and furanyl fentanyl by ing adverse effects such as respiratory potent opioid, recent evidence reveals LC-MS/MS in postmortem casework. J Anal depression is largely unexplored. that W-18 does not interact with μ-, δ-, Toxicol 40: 709–717. Naloxone (ie, Narcan) is a competi- or κ-opioid receptors; thus, effects of the Peterson AB, Gladden RM, Delcher C, Spies E, Garcia-Williams A, Wang Y et al (2016). Increases in tive μ-opioid receptor antagonist that drug will not be antagonized by nalox- fentanyl-related overdose deaths—Florida and reverses the effects of heroin, fentanyl, one (Huang et al, 2016). Ohio, 2013-2015. MMWR Morb Mortal Wkly Rep – and other opioids. Anecdotal evidence To conclude, NSOs are contributing 65: 844 849. Prekupec MP, Mansky PA, Baumann MH (2017). suggests that current naloxone dosing to the current epidemic of opioid Misuse of novel synthetic opioids: a deadly protocols (0.4–2 mg) are insufficient to overdose deaths. Basic research inves- new trend. J Addict Med 11: 256–265. rescue fentanyl overdose and previous tigations aimed at characterizing the Schumann H, Erickson T, Thompson TM, Zautcke JL, Denton JS (2008). Fentanyl epidemic in Chicago, research shows naloxone doses up to pharmacology and toxicology of NSO Illinois and surrounding Cook County. Clin Toxicol 20 mg were required to reverse the are needed as part of a comprehensive (Phila) 46: 501–506. science-based response to the opioid Shoff EN, Zaney ME, Kahl JH, Hime GW, Boland DM effects of fentanyl during an epidemic (2017). Qualitative identification of fentanyl analogs of overdose cases in Chicago during crisis. In particular, preclinical studies and other opioids in postmortem cases by UHPLC- 2005–2006 (Schumann et al, 2008). are warranted to determine the sensi- Ion Trap-MSn. J Anal Toxicol 41: 484–492. tivity of analgesic, respiratory depres- Such observations may simply reflect Neuropsychopharmacology Reviews (2018) 43, 216–217. the need for larger doses of naloxone to sant, and lethal effects of fentanyl, doi:10.1038/npp.2017.211 reverse high fentanyl doses, but could carfentanil, and NSO to naloxone or point to interaction of fentanyl with other broader spectrum opioid antago- alternative non-opioid receptor targets nists such as levallorphan. Data from after high doses. Whether greater- such studies will help to inform the Opioidergic regulation of than-expected doses of naloxone are public, influence drug scheduling deci- pain and pleasure in required to antagonize effects of highly sions, and aid in strategies to remediate potent NSO remains an open question. effects of the drugs in emergency and human social The recent emergence of the fentanyl clinical settings. relationships analog, carfentanil, in the recreational drug market is especially troubling Affiliative bonds are the hallmark of FUNDING AND DISCLOSURE because this compound is 100 times human sociability, having evolved to more potent than fentanyl (Shoff et al, This work is generously funded by the support survival, reproduction, and 2017). The potential risk from non- Intramural Research Program of the nurturing of the offspring. Social opioid compounds in the marketplace National Institute on Drug Abuse relationships are associated with secur- is well illustrated by 4-chloro-N-[(2Z)- (NIDA) for MHB and by research ity and comfort. Such feelings could 1-[2-(4-nitrophenyl)ethyl]piperidin-2- grants from NIDA (DA06241 and serve as safety signals, promoting ylidene]benzene-1-sulfonamide (W-18). DA07242), the Mayday Fund, and the incentive motivation towards social

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...... 218 bonding. Building up on the seminal sociability. In particular, opioid recep- Lauri Nummenmaa1,2 and 1 work by Jaak Panksepp and colleagues, tor availability in the frontal cortex—a Tomi Karjalainen 1Turku PET Centre, University of Turku, Turku, recent genetic studies suggest that region involved in variety of socio- Finland; 2Department of Psychology, University of different neurochemicals including emotional processes—predicts both the Turku, Turku, Finland dopamine, oxytocin, and particularly security of romantic attachment bonds E-mail: [email protected] opioid peptides regulate different as- (Nummenmaa et al, 2015) as well as pects of sociability (Pearce et al, 2017). the tendency for prosocial expressions ...... Human positron emission tomography such as laughter in social settings Hsu DT, Sanford BJ, Meyers KK, Love TM, Hazlett (PET) studies have highlighted that the (Manninen et al, 2017). Genetic as well KE, Wang H et al (2013). Response of the mu- opioid system to social rejection and acceptance. endogenous opioid system, best known as experience-dependent plasticity of Mol Psychiatry 18: 1211–1217. for its role in pain and reward, the endogenous opioid system might Karjalainen T, Karlsson HK, Lahnakoski JM, Glerean supports also social bonding in hu- thus constitute an important precursor E, Nuutila P, Jaaskelainen IP et al (2017). Dissoci- able roles of cerebral mu-opioid and type 2 mans. Prosocial behavior, such as for trait-like differences in social beha- dopamine receptors in vicarious pain: a combined social laughter, triggers endogenous vior, including prosociality and helping PET-fMRI study. Cereb Cortex 1–10. opioid release in thalamus and insular behavior. Manninen S, Tuominen L, Dunbar RIM, Karjalainen T, Hirvonen J, Arponen E et al (2017). Social laughter cortex concurrently with increased All in all, these results extend pharma- triggers endogenous opioid release in humans. J calmness and amusement (Manninen cological work in non-human primates Neurosci 37: 6125–6131. et al, 2017). Such group-level opioid showing that opioid agonists decrease Nummenmaa L, Manninen S, Tuominen L, Hirvonen J, Kalliokoski KK, Nuutila P et al (2015). Adult release via contagious laughter, rather and antagonists increase social grooming attachment style is associated with cerebral μ- than time-consuming dyadic bonding, (analogous prosocial behavior to human opioid receptor availability in humans. Hum Brain – may have allowed humans to signifi- social laughter), suggesting a shared Mapp 36: 3621 3628. Pearce E, Wlodarski R, Machin A, Dunbar RIM (2017). cantly extend their social sphere. Yet opioidergic bonding mechanism across Variation in the β-endorphin, oxytocin, and dopa- conversely, also social rejections or humans and other primates. Further- mine receptor genes is associated with different losses may trigger similar endogenous more, the recent data show that in dimensions of human sociality. Proc Natl Acad Sci USA 114: 5300–5305. opioid activation as social bonding humans the opioid system has evolved Rutgen M, Seidel EM, Silani G, Riecansky I, Hummer (Hsu et al, 2013), paralleling the to serve not only reproductive or ma- A, Windischberger C et al (2015). Placebo analge- contribution of the opioid system to ternal dyadic bonding, but also large- sia and its opioidergic regulation suggest that empathy for pain is grounded in self pain. Proc processing of purely sensory pleasure scale affiliative bonding and altruistic Natl Acad Sci USA 112: 5638–5646. and pain in humans. Thus, the opioid behaviour such as helping triggered by — Neuropsychopharmacology Reviews (2018) 43, 217–218. system seems to modulate both moti- seeing others even unfamiliar indivi- doi:10.1038/npp.2017.200 vation towards social contacts and duals—in distress. support, and away from solitude. Most humans strive for social Capacity for vicarious experience is a contacts throughout their lifespan, key feature of human sociability: feel- and lack of social contacts has sig- Modulating Amygdala– ing others’ pain in our own mind may nificant negative consequences for create a strong urge to help others in both psychological and somatic health. Hippocampal Network distress. Fusion imaging work combin- Accordingly, properly functioning en- Communication: ing PET with functional magnetic dogenous opioid system could be an A Potential Therapy resonance imaging shows that the important precursor for psychological more opioid receptors humans have resiliency and well-being in general. for Neuropsychiatric in their brain, the more strongly their This may explain why disruption of the Disorders frontocortical areas respond to seeing endogenous opioid system by, for others’ distress (Karjalainen et al, example, heroin abuse may lead to Contextual processing imbues appro- 2017). Similarly, placebo analgesia antisocial behavior. However, the spe- priate salience to our experiences and (modulated by the opioid system) cific role of the opioid system in facilitates flexible behavioral adapta- also reduces empathy-related brain different types of social relationships tion. Dysfunction in contextualizing responses towards others’ distress (such as romantic versus affiliative) information increases the risk of in- (Rutgen et al, 2015). Accordingly, the needs to be resolved in future studies. appropriate responses to environmen- physical and vicarious pain might tal conditions and has been implicated share the same neuromolecular basis, in a broad range of psychopathologies, FUNDING AND DISCLOSURE and opioidergic neurotransmission including post-traumatic stress disor- may facilitate more complex prosocial This work was supported by the der, schizophrenia, and substance motivation than just social bonding. Academy of Finland grants #265915 abuse disorders (Maren et al, 2013). Molecular imaging studies have also and #294897 to LN, and personal grant Given the essential role of contextual established that individual differences from Päivikki and Sakari Sohlberg processing in adaptive behavior and its in endogenous opioid system function Foundation to TK. The authors declare derangement in neuropsychiatric dis- explains individual differences in no conflict of interest. orders, recent research has focused on

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