The widespread use of opioids to treat pain caused an increase in opioid dependence. Between 1999 and 2010, opioid prescriptions quadrupled, leading to a concurrent increase in opioid overdose deaths (Volkow et al., 2014), and between 2000 and 2019 approximately 550,000 people died from opioid overdoses (Center for Disease Control, 2019). The development of withdrawal symptoms after ceased opioid use is a sign of dependence. The onset of withdrawal is disruptive and unpleasant, including symptoms like aches and pain, nausea, dysphoria, and insomnia, leading to resumed opioid use to reduce the withdrawal symptoms (DSM-5). Currently, the treatment for opioid withdrawal is controlled clinical administration of long-acting opioids such as methadone and buprenorphine in place of fast-acting opioids. However, it is important to find treatments that eliminate the use of opioids and reduce the necessity for clinical administration. Exercise has been shown to reduce chronic pain for a wide variety of diagnoses (Stagg et al., 2011, Mazzardo-Martins et al., 2010, Martins et al., 2013, Kroll, 2015) and in rats, reduce nicotine-seeking after loss of nicotine self-administration (Sanchez et al., 2013). The benefit of exercise for pain and attenuation of addiction poses the question of whether it can affect opioid dependence and spontaneous opioid withdrawal symptoms. In this review, the effect of exercise during opioid dependence and withdrawal will be evaluated.

Exercise-mediated release of endogenous opioids

Evidence of endogenous opioid release during exercise is one of the main draws for the investigation of exercise for treatment of opioid dependence and withdrawal. Endogenous opioids bind opioid receptors to serve diverse functions such as pain modulation, respiratory depression, euphoria, and sedation—functions healthcare providers modulate with exogenous opioids like morphine (Shenoy & Lui, 2021). Thus, if exercise can mediate the release of endogenous opioids, administration of exogenous opioids might be reduced or avoided.

Studies examining exercise-mediated endogenous opioid release were conducted first in humans. These studies found chronically active participants had elevated serum levels of beta endorphins and adrenocorticotrophic hormone and decreased pain thresholds in healthy participants after engaging in long-distance running (Janal et al., 1984, Droste et al., 1991). Additionally, when naloxone was administered, there was a reduction in the previously elevated pain thresholds implicating opioid receptor binding by endogenous opioids. Later animal studies corroborate these findings showing that exercise increases nociceptive threshold during the tail-flick latency test (Tierney et al., 1991).

Exercise alters opioid dependence

Although the mechanism is still unclear, the release of endogenous opioids during exercise may mediate the alterations of opioid analgesia and reward during concurrent treatment with opioids and exercise. After 6 weeks of voluntary wheel running, rats experienced reduced sensitivity to the antinociceptive effects of opioids ranging in efficacy at the opioid receptor (e.g., from high to low efficacy: morphine, buprenorphine, and nalbuphine) (Smith & Yancey, 2003). Wheel running produced a larger reduction in antinociceptive sensitivity in rats that were administered less efficacious opioids (i.e., longer-lasting opioids) compared to higher efficacious opioids. Furthermore, naloxone precipitated withdrawal in exercised rats. This effect of long-term exercise upon antinociceptive sensitivity is comparable to the effects produced by chronic opioid administration upon less efficacious opioids indicating the potential activation of opioid receptor pathways by endogenous opioids (Walker & Young, 2001). However, in contradiction to this finding, Shokraviyan et al. (2014) found that exercise decreased the antinociceptive effects of opioids. This contradiction may be attributed to the duration of wheel running, as this study had rats run for only 8 days. Acute exercise may activate alternative pathways aside from endogenous opioid release implicated in the previous study. Another potential mechanism for the exercise-mediated reduction in sensitivity to morphine antinociception may be related to G-protein subunit expression (Esmaelili-Mahani et al., 2013). After 6 weeks of forced treadmill exercise, rats had decreased morphine sensitivity and decreased expression of both G-alpha_i and G-beta subunits associated with opioid receptors involved in analgesia. However, again no conclusive mechanisms have been revealed.

In addition to the effect upon opioid antinociception, exercise also reduced the rewarding effects of opioids evidenced by a reduction in the conditioned place preference (CPP) effect and self-administration of morphine in exercised rats. Morphine produces a large CPP effect in sedentary rats that was not evident in exercised rats, alluding to potential opioid receptor pathway modifications (Lett et al., 2002). Furthermore, during self-administration paradigms, forced treadmill exercise reduced self-administration of morphine regardless of if it was a short or moderate term exercise regimen (Ahmadi et al., 2018, Hosseini et al., 2009).

Exercise attenuates opioid withdrawal symptoms

After the termination of opioid administration, severe and disruptive withdrawal symptoms develop. To assess withdrawal in animal models, withdrawal symptoms specific to the animal model are monitored. In rats, opioid withdrawal symptoms include climbing, grooming, stretching, defection, teeth chattering, jumping, and shaking (Cicero et al., 2002; Kalinichev and Holtzman, 2003; Cobuzzi and Riley, 2011). Affective symptoms like anxiety and depression can also be assessed (Schulteis et al., 1998). Despite the high level of diversity, exercise was found to attenuate many of these symptoms. Forced treadmill exercise after the termination of morphine administration attenuated physical symptoms and anxious behaviors. Compared to sedentary rats undergoing naloxone-precipitated withdrawal, exercised rats displayed significantly reduced physical symptoms near saline control levels for symptoms such as climbing, grooming, stretching, teeth chattering, and shaking (Ahmadi et al., 2018). Anxious behaviors measured in the elevated plus maze test and light/dark box were also reduced in exercised rats (Shahroodi et al., 2020). Rats going through withdrawal that had been administered light to moderate exercise intensities spent more time in the open arms and in the light, indicating less anxious behavior.

Conclusions and Future Directions

Both voluntary and forced exercise regimens impact opioid dependence and withdrawal. During opioid dependence, exercise reduces rats’ sensitivity to the antinociceptive effect and reward of opioids. Once opioid dependence transitions to withdrawal with the termination of opioid administration, exercise attenuates both physical and affective symptoms. Although many studies have examined the behavioral outcomes of exercise and opioid dependence and withdrawal, the field lacks mechanistic explanations. Currently, studies investigating the hippocampus have found increased levels of brain-derived neurotropic factor (BDNF) in morphine-dependent animals and inhibition of BDNF prevented positive cognitive effects of exercise like the recovery of fear responses reduced by morphine (Miladi-Gorji et al., 2011, Malekloo et al., 2022). These studies examine mechanisms driven by exercise that provide cognitive benefits but fail to explain the other physical symptoms recovered by exercise. Furthermore, recent studies have found evidence that the endogenous opioid system may not explain the effect of exercise but rather the emerging endocannabinoid system may present a better candidate (Siebers et al., 2021). Thus, future studies must examine and compare the endogenous opioid and endocannabinoid pathways potentially initiated by exercise to conclusive and specifically implicate whether both pathways or only one mediate the effects seen here upon opioid dependence and withdrawal. Additionally, it is necessary to study the role of neuromodulators, like dopamine and serotonin, released during exercise as they modify these two pathways.

[+] References

[+] Other Work By Keziah Nguyen