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Therefore, we suggest minimizing TLR\u20104 signalling may improve breathing stability during opioid therapy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Opioid\u2010induced respiratory dysfunction is a significant public health burden. While respiratory effects are mediated via mu opioid receptors, long\u2010latency off\u2010target opioid signalling through innate immune toll\u2010like receptor 4 (TLR4) may modulate essential elements of breathing control, particularly respiratory motor plasticity. Plasticity in respiratory motor circuits contributes to the preservation of breathing in the face of destabilizing influences. For example, respiratory long\u2010term facilitation (LTF), a well\u2010studied model of respiratory motor plasticity triggered by acute intermittent hypoxia, promotes breathing stability by increasing respiratory motor drive to breathing muscles. Some forms of respiratory LTF are exquisitely sensitive to inflammation and are abolished by even a mild inflammation triggered by TLR4 activation (e.g. via systemic lipopolysaccharides). Since opioids induce inflammation and TLR4 activation, we hypothesized that opioids would abolish LTF through a TLR4\u2010dependent mechanism. In adult Sprague Dawley rats, pre\u2010treatment with a single systemic injection of the prototypical opioid agonist morphine blocks LTF expression several hours later in the phrenic motor system \u2013 the motor pool driving diaphragm muscle contractions. Morphine blocked phrenic LTF via TLR4\u2010dependent mechanisms because pre\u2010treatment with (+)\u2010naloxone \u2013 the opioid inactive stereoisomer and novel small molecule TLR4 inhibitor \u2013 prevented impairment of phrenic LTF in morphine\u2010treated rats. Morphine triggered TLR4\u2010dependent activation of microglial p38 MAPK within the phrenic motor system \u2013 a key enzyme that orchestrates inflammatory signalling and undermines phrenic LTF. Morphine\u2010induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. We suggest minimizing TLR\u20104 signalling may improve breathing stability during opioid therapy by restoring endogenous mechanisms of plasticity within respiratory motor circuits.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp281362","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T11:16:06Z","timestamp":1624014966000},"page":"3771-3797","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Acute morphine blocks spinal respiratory motor plasticity via long\u2010latency mechanisms that require toll\u2010like receptor 4 signalling"],"prefix":"10.1113","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-5572","authenticated-orcid":false,"given":"Arash","family":"Tadjalli","sequence":"first","affiliation":[{"name":"Breathing Research and Therapeutics Center University of Florida  Gainesville FL USA"},{"name":"Department of Physical Therapy University of Florida  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