Morphine blocks spinal respiratory motor plasticity via mechanisms that require toll‐like receptor 4 signaling

Abstract

Opioid therapy is a common strategy for pain management; however, unfavorable side effects limit their clinical efficacy. Pro‐inflammatory cytokines oppose acute and chronic opioid‐induced analgesia and the ensuing inflammatory cascades that signal through toll‐like receptor 4 (TLR4)—pattern recognition innate immune receptors—are a significant contributor to some of the negative consequences of opioid therapy. While opioid‐induced inflammatory processes contribute to unwanted side‐effects (i.e. tolerance, dependence), it is unknown whether opioids, through pro‐inflammatory signaling, can affect the expression of plasticity within respiratory motor circuits. Adaptive plasticity within respiratory motor circuits is an important contributor to the preservation and/or restoration of respiratory function. For example, respiratory long‐term facilitation (LTF), a well‐studied model of respiratory motor plasticity, promotes breathing stabilization by increasing inspiratory drive to major breathing muscles. LTF is characterized by a long‐lasting compensatory increase in ventilation or respiratory motor nerve output triggered by exposures to acute intermittent hypoxia. Respiratory LTF is abolished by even a mild inflammation triggered by TLR4 receptor activation (e.g. via systemic lipopolysaccharides). Since opioid therapy activates TLR4 and induces neuro‐inflammation, we hypothesized that opioid delivery will abolish LTF through mechanisms that require TLR4 signaling. In adult Sprague Dawley rats, we show that acute systemic delivery of morphine, a prototypical opioid, blocks the expression of LTF in the phrenic motor system—a major motor pool that drives contractions of the diaphragm muscle. Furthermore, we show that morphine blocked phrenic LTF via mechanisms that require TLR4 signaling because systemic pre‐treatment with (+)‐naloxone—an opioid‐inactive TLR4 signaling inhibitor—restored phrenic LTF in morphine‐treated rats. Our findings suggest that loss of phrenic LTF following morphine treatment may remove an important stabilizing factor for breathing, potentially contributing to respiratory failure. Thus, attenuation of inflammatory signaling by opioid‐inactive compounds may help restore endogenous mechanisms of spontaneous plasticity within respiratory circuits, thereby minimizing opioid‐induced respiratory depression.Support or Funding InformationNIH SPARC Initiative (OT2OD023854)