**8.3 Abuse potential**

220 Neuroscience – Dealing with Frontiers

preference for quinine solutions (Kovacs et al., 2005). Unlike ligands with highest activity for the MOP-R (such as naltrexone), KOP-R, NOP-R and SIG-R, the ligands which have selective for DOP-R appear to have greater selectivity for ethanol consumption with reduced activity on general consummatory behavior, such as food, sugar or water consumption (Barson et al., 2009; Barson et al., 2010; Froehlich et al., 1991; Krishnan-Sarin et al., 1995b). Central administration of naltrexone, nor-BNI and -funaltrexamine, but not naltrindole, reduces intake of sucrose solutions in rats (Beczkowska et al., 1992; Koch et al., 1995). Furthermore, central administration of naltrexone, naloxonazine and nor-BNI, but not naltrindole or the DOP-R agonis DALCE, reduces fat intake in food-deprived rats (Koch & Bodnar, 1994). The enkephalinase inhibitor, thiorphan, increased ethanol, but not water, intake in alcohol-preferring rats (Froehlich et al., 1991). Central administration of the DOP-R agonist, DALA, to rats selectively increased ethanol consumption over food and water in comparison to non-selective actions on ethanol intake by the MOP-R agonists, DAMGO and morphine (Barson et al., 2009; Barson et al., 2010). The naltrexone-derived DOP-R antagonist, SoRI-9409, was shown to be much more effective and selective in reducing ethanol consumption than naltrexone such that, unlike naltrexone, SoRI-9409 did not reduce water intake and did not reduce sucrose intake in doses that effectively reduced ethanol intake (Nielsen et al., 2008). Although one study found that the DOP-R antagonist, naltrindole, reduced ethanol and saccharin, but not water, consumption in rats (Krishnan-Sarin et al., 1995a), further studies by these same researchers showed that the DOP-R antagonist, naltriben, reduced the intake of solutions containing ethanol with saccharin and ethanol with quinine but no effects on the intake of either saccharin or quinine solutions alone (Krishnan-Sarin et al., 1995b). Taken together, these studies suggest that compounds with activity at the DOP-R selectively alter ethanol intake over general consummatory

A major problem in treating AUDs is the high rate of relapse which is usually triggered by stress and anxiety (Sinha, 2007; Sinha & Li, 2007). Recent preclinical studies have suggested that potential new pharmacotherapies for AUDs act by reducing anxiety and cravings in alcohol-dependent subjects (George et al., 2008; Heilig et al., 2010). Treatment options to control stress and anxiety disorders include benzodiazepines, which carry the risk of abuse potential, and antidepressants, which demonstrate a relative large interindividual variability in terms of drug response (O'Brien, 2005; Tiwari et al., 2009). Studies investigating the roles of opioid receptors in anxiety and stress indicate that the DOP-R plays a significant role. DOP-R knockout mice have increased anxiety (Filliol et al., 2000). In comparison, rats administered the DOP-R agonist, SNC80 have increased anxiolytic activity, an effect that is reversed by naltrindole (Perrine et al., 2006; Saitoh et al., 2004). Naltrindole was found to have anxiogenic activity when given in higher, but not lower doses (Perrine et al., 2006; Saitoh et al., 2004) although the DOP-R antagonist, SoRI-9409 has neither anxiogenic nor anxiolytic activity (Nielsen et al., 2008). In contrast, -funaltrexamine and nor-BNI did not produce any anxiogenic or anxiolytic effects, suggesting the MOP-R and KOP-R do not play a role in anxiety states (Saitoh et al., 2004). Following the forced swim test, plasma levels of the stress hormone, corticosterone are the same, in triple opioid receptor knockout (MOP-R, DOP-R, KOP-R) knockout and wild-type mice (Contet et al., 2006). This suggests that opioid

behavior.

**8.2 Anxiety and stress** 

An issue with the use of pharmacotherapeutics for the treatment of addiction is the incidence of potential abuse of the therapeutic itself. For example, the MOP-R agonist methadone, which is used to treat heroin addiction, has been reported to be widely abused (Li et al., 2011; Simonsen et al., 2011a; Simonsen et al., 2011b; Tormoehlen et al., 2011). Although the use of "substitution" therapy with opioid agonists has been effective for some patients, it has remained controversial (Gerra et al., 2009; Ling et al., 1994; Rhodes & Grossman, 1997). However, as naltrexone induces aversive side-effects in humans and conditioned place aversion in rats (Mitchell et al., 2009), it does not appear to be rewarding itself. Furthermore, naltrexone attenuates the expression of ethanol place conditioning in mice (Middaugh & Bandy, 2000). MOP-R agonists increase and MOP-R antagonists decrease, respectively, ethanol-induced CPP in rats (Matsuzawa et al., 1998; Matsuzawa et al., 1999a; Matsuzawa et al., 1999b). In comparison, activation of the KOP-R is associated with general aversive activity in rats (Shippenberg & Herz, 1986) and induces dysphoria in humans (Kumor et al., 1986; Pfeiffer et al., 1986; Rimoy et al., 1994). The KOP-R agonist, U50488, attenuates ethanol-induced CPP in rats (Matsuzawa et al., 1999a). KOP-R agonists, therefore, do not appear to be carry the risk of abuse potential. In comparison, KOP-R antagonists, such as nor-BNI do not produce CPP or CPA (Mitchell et al., 2005; Sante et al., 2000) although nor-BNI did increase ethanol-induced CPP in one study (Matsuzawa et al., 1999a).

As described earlier, DOP-R agonists increase and DOP-R antagonists attenuate, respectively, ethanol-induced CPP in rats (Bie et al., 2009; Matsuzawa et al., 1998; Matsuzawa et al., 1999a; Matsuzawa et al., 1999b) and DOP-R antagonists can make a nonaversive dose of alcohol aversive (Froehlich et al., 1998). DOP-R antagonists administered alone do not induce CPP or CPA (Nielsen et al., 2008) suggesting they are not rewarding themselves. The increase in the rewarding actions of ethanol by DOP-R agonists may contribute to the altered levels of ethanol consumption following treatment with DOP-R agonists, as described above (Barson et al., 2009; Barson et al., 2010; Margolis et al., 2008; van Rijn et al., 2010; van Rijn & Whistler, 2009). Furthermore, DOP-R (and MOP-R) agonists have been shown to be rewarding themselves such that DPDPE is self-administered into the VTA of rats (Devine & Wise, 1994; McBride et al., 1999). Activation of DOP-R (and MOP-R) leads to increased basal dopamine release in brain regions involved in the reward pathway

The Role of Delta Opioid Receptors in Ethanol Consumption

**9. Conclusions** 

**10. Acknowledgements** 

**11. References** 

Jeffrey Simms for critically reviewing the manuscript.

*J Pharmacol,*Vol.230, No.2, (Jan 12), pp. 239-241

*Psychopharmacology,*Vol.100, No.4, 451-458, ISSN 0033-3158

and Seeking: Implications for New Treatments for Alcohol Use Disorders 223

naltrindole, naltriben and 7-benzylidenenaltrexone, suggesting the convulsive activity by BW373U86 is DOP-R-mediated (Broom et al., 2002a; Broom et al., 2002b; Comer et al., 1993), Furthermore, the BW373U86-induced convulsive effects were reduced by naltrexone given in very high doses (10-100 mg/kg), doses of which would presumably block DOP-R (Comer et al., 1993). However, recent studies in the pursuit of the development of DOP-R agonists for the treatment of pain and depression have discovered new DOP-R agonists, such as KNT-127, which are devoid of convulsant activity, while still retaining analgesic and antidepressant activity (Saitoh et al., 2011). However, since inhibition of the DOP-R reduces the incidence of DOP-R agonist-induced convulsive activity, the use of DOP-R antagonists may also provide an additional benefit for alcohol-

Although naltrexone has the most consistent effects in reducing alcohol consumption, it only effectively prevents relapse in a subset of alcohol-dependent patients. Preclinical studies suggest that potential new therapeutics that target the DOP-R may offer advantages in the treatment and prevention of relapse compared with agents that have activity for the other opioid receptor subtypes. DOP-R agonists may offer advantages for the relief of ethanol withdrawal-induced anxiety and hyperalgesia. DOP-R antagonists appear to effectively and selectively reduce ethanol consumption and seeking with limited effects on general consummatory behavior. The particular effectiveness of DOP-R antagonists in models of high ethanol consumption and relapse to ethanol-seeking may represent an alternative therapeutic strategy for reducing heavy drinking and relapse to alcohol abuse. Furthermore, DOP-R antagonists do not appear to have any abuse potential, effects on pain perception or inductions of convulsive activity. Taken together, the DOP-R represents a very

dependent patients to prevent seizures in the early stages of withdrawal.

promising candidate therapeutic target for the treatment of alcohol use disorders.

This work was supported by funding from the State of California for Medical Research through UCSF (to SEB). CKN was supported in part by the Essel Foundation as a National Alliance for Research on Schizophrenia and Depression Young Investigator. We thank

Acquas, E.; Meloni, M. & Di Chiara, G. (1993). Blockade of delta-opioid receptors in the

Adams, J.U. & Holtzman, S.G. (1990). Tolerance and dependence after continuous morphine

Altshuler, H.L.; Phillips, P.E. & Feinhandler, D.A. (1980). Alteration of ethanol selfadministration by naltrexone. *Life Sci,*Vol.26, No.9, (Mar 3), pp. 679-688

nucleus accumbens prevents ethanol-induced stimulation of dopamine release. *Eur* 

infusion from osmotic pumps measured by operant responding in rats.

(Borg & Taylor, 1997; Devine et al., 1993a; Devine et al., 1993b; Herz, 1997; Vetulani, 2001). The DOP-R agonists, BW373U86 and SNC80, induce significant CPP in rats, effects of which are reversed by pretreatment with naltrindole given in doses which does not modify preference when given alone (Ehlers et al., 1999). Collectively, as DOP-R antagonists inhibit the actions of ethanol-induced endogenous opioids and subsequent dopamine release, and also reduce the rewarding effects of ethanol without being rewarding themselves, these compounds do not appear to be prone to potential abuse.

#### **8.4 Pain perception**

Hyperalgesia has been commonly noted following alcohol withdrawal in alcohol-dependent patients (Dina et al., 2008; Gatch, 2009; Jochum et al., 2010) and so analgesic medications may be prescribed to provide pain relief in the early stages of withdrawal (Gillman & Lichtigfeld, 1990). As naltrexone has been shown to block morphine-mediated analgesia in mice (Yan et al., 2003) and in rats (Nielsen et al., 2008), naltrexone treatment may therefore interfere with pain-relieving medications. Furthermore, as naltrexone can precipitate withdrawal symptoms in opioid-dependent rats (Adams & Holtzman, 1990) and monkeys (Paronis & Bergman, 2011), naltrexone treatment may potentially lead to exacerbation of withdrawal-induced hyperalgesia in alcohol-withdrawn patients. Although opioid receptor agonists with highest affinity for the MOP-R, such as morphine and methadone, have been widely used in the clinic for the treatment of pain (Nissen et al., 2001; Peng et al., 2008), preclinical studies have also demonstrated that KOP-R and DOP-R both play roles in analgesia. The administration of opioid agonists acting at the KOP-R (Leighton et al., 1988; Nielsen et al., 2007; Ross & Smith, 1997; Tiseo et al., 1988) and DOP-R (Kamei et al., 1994; Kamei et al., 1997; Scherrer et al., 2004) produce analgesia and anti-allodynia in rats and mice. Furthermore, co-administration of morphine with a KOP-R or a DOP-R agonist results in enhanced analgesia (Ross et al., 2000; Suzuki et al., 1995). A recent study showed that the DOP-R antagonist, SoRI-9409, does not reduce morphine-mediated tail-flick analgesia compared to the significant reduction in morphine-mediated analgesia by naltrexone (Nielsen et al., 2008). When administered alone, SoRI-9409, did not produce tail-flick analgesia or hyperalgesia (Nielsen et al., 2008) but did produce analgesia in the acetic acid writhing test in mice (Wells et al., 2001). Although DOP-R antagonists attenuate DOP-R agonist-mediated analgesia in mice (Kamei et al., 1995; Tseng et al., 1997), they do not block the analgesic effects of clinically used opioid analgesics (Nielsen et al., 2008).

#### **8.5 Seizure thresholds**

Seizures have commonly been observed following alcohol withdrawal in alcoholdependent patients (Amato et al., 2011; Eyer et al., 2011a; Eyer et al., 2011b; Kim et al., 2011). Treatment options to control alcohol-withdrawal convulsions include carbamazepine, valproate and benzodiazepines (Amato et al., 2011; Eyer et al., 2011a) which all have a number of undesirable side-effects. A number of studies have indicated that activation of the DOP-R is associated with an increased incidence of convulsive activity. The DOP-R agonists, SNC80 and BW373U86, induce convulsions in mice (Broom et al., 2002b; Comer et al., 1993), rats (Broom et al., 2002a) and monkeys (Dykstra et al., 1993; Negus et al., 1994). The BW373U86-induced convulsant activity was reduced by naltrindole, naltriben and 7-benzylidenenaltrexone, suggesting the convulsive activity by BW373U86 is DOP-R-mediated (Broom et al., 2002a; Broom et al., 2002b; Comer et al., 1993), Furthermore, the BW373U86-induced convulsive effects were reduced by naltrexone given in very high doses (10-100 mg/kg), doses of which would presumably block DOP-R (Comer et al., 1993). However, recent studies in the pursuit of the development of DOP-R agonists for the treatment of pain and depression have discovered new DOP-R agonists, such as KNT-127, which are devoid of convulsant activity, while still retaining analgesic and antidepressant activity (Saitoh et al., 2011). However, since inhibition of the DOP-R reduces the incidence of DOP-R agonist-induced convulsive activity, the use of DOP-R antagonists may also provide an additional benefit for alcoholdependent patients to prevent seizures in the early stages of withdrawal.
