ABSTRACT
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1ß (IL-1ß). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.
Subject(s)
Chronic Pain/metabolism , Inflammasomes/metabolism , Microglia/metabolism , Morphine/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neuralgia/metabolism , Spinal Cord Dorsal Horn/metabolism , Animals , Chronic Pain/pathology , Chronic Pain/physiopathology , Clozapine/analogs & derivatives , Clozapine/pharmacology , Interleukin-1beta/metabolism , Male , Microglia/pathology , Neuralgia/pathology , Neuralgia/physiopathology , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn/pathology , Spinal Cord Dorsal Horn/physiopathologyABSTRACT
Cell Chemical Biology has recently added several advisory board members from China in an effort to better represent our authorship and readership. In this Voices piece, a few of the new members introduce themselves, give their perspective on challenges and opportunities in chemical biology, and discuss how they plan to contribute to the field through their new position.