Risks of Impaired Organ Protection with Inhibiting Transient Receptor Potential Vanilloid 1

With great interest we recently read the manuscript by Garami et al.,¹  which illustrates how the transient receptor potential vanilloid 1 antagonists, AMG 517 and ABT-102, prevent anesthesia-induced hypothermia and simultaneously decrease opioid requirements for postoperative hyperalgesia in rodents. These preclinical data suggest that transient receptor potential vanilloid 1 antagonists may be useful as opioid-sparing modalities for analgesia intraoperatively and postoperatively while also providing hyperthermia to pharmacologically counteract anesthetic-induced hypothermia. This finding is novel and may lead the way to developing new opioid-sparing drugs to be used perioperatively. However, it would be of benefit if the authors may comment on some of the potential shortcomings we see of using transient receptor potential vanilloid 1 antagonists during surgery and the potential strategies to overcome these barriers we outline below.

For example, intravenous administration of transient receptor potential vanilloid 1 antagonists may also block endogenous mechanisms of organ protection. It is important to recognize that untreated transient receptor potential vanilloid 1 knockout mice or mice treated with a transient receptor potential vanilloid 1 inhibitor subjected to ischemia-reperfusion injury using an isolated heart model produce impaired functional recovery compared to wild-type transient receptor potential vanilloid 1 mice.²  Further, in a deoxycorticosterone acetate–salt hypertension model, ablation of transient receptor potential vanilloid 1 gene in the C57BL/6 mice exacerbates renal damage compared to deoxycorticosterone acetate–salt-treated wild-type mice, indicating that transient receptor potential vanilloid 1 may constitute a protective mechanism against end-organ damage induced by hypertension.³  Additionally, transient receptor potential vanilloid 1 channel activation reduces organ injury for the lung,⁴  kidney,⁵  and brain.⁶  Furthermore, transient receptor potential vanilloid 1 antagonists may interfere with the agents or interventions administered perioperatively that may decrease organ injury, such as a surgical incision or opioids that appear to provide their protective effect by a transient receptor potential vanilloid 1–dependent mechanism.⁷  Therefore, using transient receptor potential vanilloid 1 antagonists for surgeries undergoing organ reperfusion injury or in a patient population with cardiovascular disease who are at higher risk of having an intraoperative myocardial infarction may possibly cause an unwanted side effect of exacerbating organ injury during ischemia-reperfusion or block the abilities for agents we commonly administer in the operating room to limit cellular injury.

Hypothermia induced by transient receptor potential vanilloid 1 activation is also considered as a promising intervention for organ protection. Rinvanil, a transient receptor potential vanilloid 1 agonist, induces mild hypothermia (33°C), which is associated with 34% smaller cerebral infarct size volumes in mice subjected to transient middle cerebral artery occlusion versus vehicle-treated controls.⁵  Thus, drugs specifically inhibiting transient receptor potential vanilloid 1 may interrupt the benefits of hypothermia associated with organ protection.

In conclusion, it is important to consider whether blocking transient receptor potential vanilloid 1 to reduce opioid requirements or raise body temperature may have some unknown risks.

Funded by National Institutes of Health, Bethesda, Maryland, grant Nos. HL109212 and GM119522 (to Dr. Gross), the Priority Department of Second Affiliated Hospital of Anhui Medical University, Hefei, China (to Dr. Wu), and the China Scholarship Council (201608535052; to Dr. Qian).

Dr. Gross holds a U.S. patent titled “Peptide Modulators of Specific Calcineurin Protein–Protein Interactions.” The other authors declare no competing interests.