Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

Abstract

Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.

Paradoxical changes in brain reward status during oxycodone self‐administration in a novel test of the negative reinforcement hypothesis

“…The increased intracranial self-stimulation (ICSS) thresholds observed during sequential daily extended-access self-administration sessions in this study were consistent with prior results showing brain reward changes following extended access to self-administration of several different drugs (Ahmed et al, 2002;Jang et al, 2013;; this similarity is emphasized in the eight consecutive day experiment (Figure 4a). This pattern has been interpreted as key support for the negative reinforcement hypothesis in those reports (also see Pantazis et al, 2021;Zernig et al, 2007). The interpretation that dependence-related negative affect drove the escalated oxycodone IVSA in this study is further supported by the finding that when ICSS thresholds were elevated, the self-administration of oxycodone (or heroin) for 1 h (Figure 5), or non-contingent injection of an appropriate dose of oxycodone (Figure S2), was able to normalize thresholds towards baseline.…”

A neuroeconomic signature of opioid craving: How fluctuations in craving bias drug-related and nondrug-related value

“…Also distinct from food craving, which can be positively motivating [83], opioid craving is typically experienced as a negative affective state [36][37][38][39][40][41]. To determine the influence of concomitant negative mood, we continuously assessed participants' current stress, happiness, and boredom.…”

“…Craving for drugs, particularly opioids, co-occurs with a mixture of (mostly negative) affective experiences [36][37][38], sometimes referred to as 'hyperkatifeia' [39][40][41]. However, negative mood has incidental effects in decision-making [42][43][44], and could be expected to shift value globally rather than specifically for the drug, increasing the attractiveness of both drug-and nondrugrelated options.…”

Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice

“…Although sex differences in opioid dependence have been reported in humans and rodents ( Zachry et al, 2019 ; Marchette et al, 2021 ; Pantazis et al, 2021 ), most studies were conducted in male subjects. Previous studies found that female opioid-dependent mice and rats exhibited similar levels of somatic signs of naloxone-precipitated heroin withdrawal compared with male opioid-dependent mice and rats ( Cicero et al, 2002 ; Towers et al, 2019 ).…”