Page 45 - CASA Bulletin of Anesthesiology 2019 Vol 6 No 5

Vol.6, No.5, 2019

DOI: 10.31480/2330-4871/099
recover from primary illness in three months. Patients secondary messenger activating protein kinase A (PKA).
who are on opioids at that time are more likely entering In turn, PKA phosphorylates cAMP binding responsive
the chronic phase of the drug use. The intention of this element (CREB). CREB is critical in regulating several
review is to demonstrate several observations poten- genes which are critical in long-term potentiation and
tially affecting the administration of anesthesia during synapse formation. This is a “classical” series of molec-
surgical procedures. ular event after opioid binding [8]. However, prolonged
Our review is intended for perioperative medical exposure of opioid receptor triggers different molecular
specialists. Often, for the anesthesiologist, the issue of events from short term stimulation.
chronic opioids use becomes evident during the periop- During chronic opioid use, the opioid receptors are
erative management of pain. Considering significant exposed to repeated activation and/or prolonged stim-
body of evidence we will not discuss how chronic opi- ulation. Typically, this will trigger several mechanisms
oids use will affects perioperative pain management altering the physiologic effect of opioids, in addition to
unless it is related to molecular level mechanisms. changes in pharmacokinetic performance. One of the
However, opioids have several properties outside pain mechanisms regulating exposure of opioid receptors to
modulation. Most of these effects are often discounted ligands is phosphorylation. One study found that mice
during perioperative delivery of the anesthesia. The in- chronically exposed to morphine exhibited decreased
creasing emphasis on rapid recovery, durability of the PKA-induced phosphorylation of μ-opioid receptors
treatment, and long-term outcome of medical interven- leading to a 50% downregulation in μ-opioid receptors,
tions may soon put anesthesiologist in the situation to revealing a potential mechanism for morphine tolerance
consider the long-term effect of opioid use on perioper- [9]. The second mechanism regulating chronic exposure
ative planning. to opioids is ß-arrestin-mediated endocytosis of the re-
Methodology ceptor reducing the effective sensing of opioid ligands
[10,11]. It is important to note that the total number
The purpose of this review is to critically review data of receptors remains the same in the brain since trans-
on the effect of chronic opioids use on the performance location, not digestion, of receptors is primary mecha-
of several systems. A PubMed, International Scientific nism [12]. Downregulation is also not a simple process
Indexing (ISI), and Web of Science search was conduct- of reducing the number of open to stimulation recep-
ed utilized search terms and synonyms of long-term, tors, but rather qualitatively changes the physiological
opioids, and immunologic effects. Non-English language response to opioids via a variety of mechanisms. In ad-
articles were excluded. Bibliographies of retrieved stud- dition to phosphorylation, the chronic exposure to opi-
ies were searched for other relevant studies. Articles
were reviewed for their contribution to understanding oids leads to preferential formation μ-δ heterodimers
the long-term effects of chronic opioids, with priority in critical areas of the central nervous system [13,14].
given to clinical trials, large retrospective studies, and Formation of heterodimers significantly impairs ligand
prospective studies in the basic sciences. A total of 56 binding and reduces some of the downstream effects of
original research studies were reviewed for their rele- the heterodimerized receptor. Milan-Lobo, et al. (2013)
vance and utilized in this review. The following themes demonstrated the significance of heterodimer forming
are addressed in this review: 1) The effect of chronic on pain perception and the role of the antagonists of
opioid use on opioid receptors 2) The effect of chronic μ-δ heterodimers on improving the reduced analgesic
opioid use on the regulation and performance of organ effects of chronic opioid use [15].
systems. The translational importance of these findings
Receptor Mechanisms and Prolonged Stimula- warrants further research. Theoretically, these mech-
anisms (phosphorylation, endocytosis, heterodimer
tion formation) may prevent hyperactivation of cAMP due
Opioids act through seven-transmembrane G-cou- to chronic receptor stimulation. cAMP hyperactivation
pled receptors. Binding of the ligand results in the re- would trigger several downstream effects like hyper-
lease of guanosine diphosphate (GDP) from the G α-sub- activation of extracellular signal-related kinase (Erk),
unit followed by binding of guanosine triphosphate a predominantly inflammatory pathway. However, the
(GTP). This replacement results in significantly lower activation of Erk is significantly downregulated during
affinity of to the Gßγ and separation. Once lipid anchors chronic exposure of opioids, suggesting an interplay of
are cleaved, the active G subunit inhibits adenyl cyclase other mechanisms. Understanding why Erk is downreg-
activity resulting in an increase in cyclic adenosine mo- ulated in this particular situation is critical to under-
nophosphate (cAMP). In addition, hyperpolarization of stand the immunoinhibitory effect of opioids, consider-
the cellular membrane is mediated by activation of in- ing that Erk is an essential component of inflammatory
ward rectifying potassium channel (K ). cAMP acts as a pathways [16]. A similar mystery is encountered in case
ir
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