**9. Conclusions**

222 Neuroscience – Dealing with Frontiers

(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

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Bergman, 2011), naltrexone treatment may potentially lead to exacerbation of withdrawal-induced hyperalgesia in alcohol-withdrawn patients.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).

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

compounds do not appear to be prone to potential abuse.

**8.4 Pain perception** 

**8.5 Seizure thresholds** 

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