The effects of five clinically relevant narcotic drugs on the generation of spontaneous augmented (sigh) breaths.
Authors: Kortes Cameron T. , Grzesek Kimberly , Bell Harold James 
Published: November 2023

The prototypical μ‐opioid agonist, morphine, powerfully suppresses spontaneous augmented breaths (ABs). We previously found that this effect occurs at relatively low‐to‐moderate dosages, where traditional parameters of eupneic breathing (VT and f) are not overtly affected. Based upon the heterogeneity of pharmacological properties among commonly prescribed opioid medications, we hypothesized that the suppression of ABs would be significantly different in the presence of opioid drugs other than morphine. To test this, we studied 6 adult male rats (534±47g, range=402–637g) using a randomized cross‐over repeated‐measures design to evaluate the effects of 5 common narcotics on the rate of ABs during spontaneous breathing in unanesthetized and unrestrained adult male rats, monitored using hybrid sealed‐chamber and open‐flow plethysmography. Drugs were administered via s.c. injection at the following doses: Morphine: 0, 1.0, 2.0, 3.0 mg/kg; Fentanyl: 0, 0.02, 0.03, 0.04 mg/kg; Methadone: 0, 1.0, 2.5, 4.0 mg/kg; Buprenorphine: 0, 0.01, 0.03, 0.05 mg/kg; Oxycodone: 0, 0.5, 1.0, 1.5 mg/kg (0 mg/kg = saline sham dose). All animals received all drugs and dosages in randomized order. Doses were chosen to achieve a range up to and including analgesic effectiveness to prolong tail flick latency 2‐to‐3 fold over the sham injection. A tail flick analgesiometer was used to evaluate tail flick latency 15‐minutes post‐injection, followed by respiratory monitoring in ambient room air conditions for 30 minutes. Each animal completed a trial involving one dosage of one drug on a given day, with at least 48 hours between consecutive sessions. Drugs did not depress tidal volume or frequency of eupneic breathing. The baseline number of ABs observed following control injections for each drug condition were not different, ranging from 6.5 ± 1.4 to 7.3 ± 1.6 ABs/15mins, p=0.912. Each drug tested significantly decreased the number of spontaneous ABs in a dose‐dependent manner. The number of ABs observed at the highest drug dosages were 1.5 ± 1.3 (mor), 1.3 ± 1.0 (fen), 0.8 ± 1.2 (met), 0.0 ± 0.0 (bup), and 1.7 ± 1.2 (oxy) ABs/15mins (p<0.001 for all changes vs sham). The relationship between ABs and analgesic effect (i.e. %increase in tail flick latency vs. % of ABs remaining in the breathing rhythm) followed a 2‐parameter single exponential decay model. Significant relationships were identified between analgesic effect and suppression of ABs for all drugs tested (p<0.05) with the exception of oxycodone wherein the relationship narrowly failed to reach statistical significance (p=0.058). The strongest relationship existed within the buprenorphine condition (rs=.764, p<0.001). Buprenorphine also yielded the lowest analgesic effect required to produce a 50% suppression in ABs (observed at 16% prolongation in tail flick latency). Our results demonstrate that the suppression of ABs is a ubiquitous side effect of common narcotic drugs across the low‐moderate analgesic range, and is therefore unlikely to be mitigated by selective avoidance of specific opioids/opiates. Further, the unique potency of buprenorphine in suppressing ABs suggests that complex opioid receptor interactions may be of key mechanistic importance in mediating this effect.Support or Funding InformationCK was supported by a Summer Scholars Research Program Award through the CMU College of Medicine. HB received research support from an Early Career Award through the Office of Research and Sponsored Programs at CMU, and operating funds from the CMU College of Medicine.