**4. Conclusions**

It is unclear why p38 MAPK is merely involved in the expression of cocaine CPP when the inhibitor is administered before the post-conditioning test in a drug-free state [20], i.e., when the animals encounter drug-associated cues, but not in the learning required for the rewarding properties of cocaine. It was previously observed that KOR activation before the presentation of cocaine-associated cues enhances approach behaviors to those cues [59], possibly via activation of p38 signaling pathway. This potentiation of cocaine CPP by KOR activation does not result from an enhancement of associative learning mechanisms, as KOR activation only occurred before the final preference test after the associative learning phases were already complete. Conversely, the inhibition of p38 signaling only after the post-conditioning test might reduce the rewarding value of cocaine-associated contexts. More studies are needed to emphasize this possibility, in particular because expression of cocaine CPP did not increase the levels of pp38 in the regions of NAc core or NAc shell [34]. Yet, the study by [20] suggested that p38 MAPK-mediated norepinephrine transporter (NET) up-regulation is linked to cocaine-induced CPP.

It appears that p38 MAPK activation is more closely associated to stress-induced aversive responses rather than drug e ffects per se. Mostly, studies show that p38 MAPK activation is only involved in cocaine reward, predominantly when promoted by stress. However, it remains open to discussion how p38 MAPK is implicated in CPP morphine acquisition. The first explanation could be that morphine might activate KOR as well as μ opioid receptors (MOR). Indeed, it has been reported that morphine is weakly selective to the MOR and possesses a ffinity to δ opioid receptors (DOR) and KORs [60,61]. This explanation is further supported by the fact that naloxone, a non-selective opioid antagonist, could block the acquisition of morphine CPP [62]. However, the rewarding e ffects of morphine are abolished in MOR-deficient animals [63], thereby showing that MOR gene product is the molecular target of morphine in vivo. In addition, the k-opioid antagonist nor-binaltorphimine did not a ffect morphine CPP [64]. Remarkably, it appears that DORs, rather than KORs, are implicated in the acquisition of morphine reward; as the administration of the selective delta-2-opioid receptor antagonist naltriben prior to morphine was able to block morphine-induced CPP [65], suggesting that this first explanation is unlikely to occur. The second explanation might be that opioid receptor-mediated p38 phosphorylation has also been demonstrated for MORs [66]. MOR opioids could to some extent induce activation of p38 [67,68]. It is therefore plausible that inhibition of p38 signaling during morphine training could abolish acquisition but not before the post-conditioning test, after that morphine acquisition was already established.

In conclusion, understanding the molecular and cellular mechanisms that control stress-induced behaviors could explain the neurobiological mechanisms involved in depression and addiction-like behaviors and provides insight to potential therapeutic targets. Emerging evidence demonstrates a role for p38 MAPK in depression, anxiety, and addiction relapse induced by stress. Targeting the p38 MAPK pathway for therapeutic advantage might appear standard, given the broad range of pathologies in which this pathway is implicated. However, the pathology-specific functions and targets of p38 MAPK together with its interaction with other intracellular regulatory pathways initiates many challenges to exploiting this pathway for therapeutic benefit [5]. Indeed, p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. Here, we opine that p38 MAPK inhibitors are of growing interest as possible therapeutic interventions against stress-related disorders by potentially increasing resilience against stress and addiction relapse induced by adverse experiences.

**Author Contributions:** Writing—original draft preparation, R.E.R.; writing—review and editing, I.M.A. and A.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** The work by our group described in this article was funded by Austrian Science Fund (FWF). Grant Numbers: P23824-B18; P27852-B21 and T758-BBL.

**Acknowledgments:** The authors wish to thank Ingie Zakaria for her assistance in English editing. **ConflictsofInterest:** Theauthorsdeclarenoconflictofinterest.
