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Review
. 2022 Jun 27;11(7):1267.
doi: 10.3390/antiox11071267.

Opioids and Vitamin C: Known Interactions and Potential for Redox-Signaling Crosstalk

Mackenzie Newman  1 , Heather Connery  1   2 , Jonathan Boyd  1   2
Affiliations
Review

Opioids and Vitamin C: Known Interactions and Potential for Redox-Signaling Crosstalk

Mackenzie Newman et al. Antioxidants (Basel). .

Abstract

Opioids are among the most widely used classes of pharmacologically active compounds both clinically and recreationally. Beyond their analgesic efficacy via μ opioid receptor (MOR) agonism, a prominent side effect is central respiratory depression, leading to systemic hypoxia and free radical generation. Vitamin C (ascorbic acid; AA) is an essential antioxidant vitamin and is involved in the recycling of redox cofactors associated with inflammation. While AA has been shown to reduce some of the negative side effects of opioids, the underlying mechanisms have not been explored. The present review seeks to provide a signaling framework under which MOR activation and AA may interact. AA can directly quench reactive oxygen and nitrogen species induced by opioids, yet this activity alone does not sufficiently describe observations. Downstream of MOR activation, confounding effects from AA with STAT3, HIF1α, and NF-κB have the potential to block production of antioxidant proteins such as nitric oxide synthase and superoxide dismutase. Further mechanistic research is necessary to understand the underlying signaling crosstalk of MOR activation and AA in the amelioration of the negative, potentially fatal side effects of opioids.

Keywords: crosstalk; metabolism; mu opioid receptor; opioids; oxidative stress; signaling; vitamin C.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of common opioids. Some prominent clinical opioids include morphine, codeine, hydrocodone, oxycodone, hydromorphone, oxymorphone, methadone, and tramadol, while heroin and fentanyl are most often subject to illicit use. Structures are derived from [35].
Figure 2
Figure 2
Tyramine moiety in morphinoid pharmacophore. (A) Morphinoid pharmacophore with tyramine moiety highlighted. (B) Reaction mechanism for oxidation of tyramine (adapted with permission from Ref. [56]. 2013, American Chemical Society). Reversible oxidation of tyramine (left) leads to a neutral, reactive radical intermediate species (middle) which can quench free radicals such as superoxide, hydroxide radical, nitrite radical “Y”, yielding a substituted phenol (right). Reaction of tyrosine, a tyramine-containing amino acid, with the nitrite radical or peroxynitrite forms nitrotyrosine, a residue disruptive to protein–protein interactions.
Figure 3
Figure 3
Potential crosstalk between MOR activation and AA. Purple circles indicate effect of MOR activation and orange circles indicate effect of AA; “+” is an increase, “—” is a decrease, and “+/—” indicates mixed effects from literature. Pointed arrowheads indicate activation and flat arrowheads indicate decreased activity. Solid arrows indicate direct effects and dashed arrows indicate indirect/distal effects. Green boxes are enzymes and red are transcription factors. Transcription of example redox genes and proteins listed in the nucleus is affected by their linked transcription factors. MOR: μ opioid receptor; SVCT1/2: sodium-dependent vitamin C transporters 1/2; αi/o: Gαi/o subunit; β/γ: Gβ/γ subunit; PLC: phospholipase C; IP3: inositol 3-phosphate; ER: endoplasmic reticulum; CaM: calmodulin; NOS: nitric oxide synthases; BH3: trihydrobiopterin; BH4: tetrahydrobiopterin; AC: adenylate cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; pro3/4OHase: prolyl 3- and prolyl 4-hydroxylases; aspOHase: asparaginyl hydroxylase.
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Grants and funding

This research was funded by Defense Threat Reduction Agency grant number HDTRA1-20-1-0008.