TY - JOUR
T1 - Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats
AU - Muscat, Stephanie M.
AU - Deems, Nicholas P.
AU - D'Angelo, Heather
AU - Kitt, Meagan M.
AU - Grace, Peter M.
AU - Andersen, Nathan D.
AU - Silverman, Shaelyn N.
AU - Rice, Kenner C.
AU - Watkins, Linda R.
AU - Maier, Steven F.
AU - Barrientos, Ruth M.
N1 - Funding Information:
This work was supported, in part, by a grant from the National Institute on Aging RF1AG028271 to R.M.B. & S.F.M. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and National Institute of Alcohol Abuse and Alcoholism (NIAAA).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2
Y1 - 2021/2
N2 - Postoperative cognitive dysfunction (POCD) is the collection of cognitive impairments, lasting days to months, experienced by individuals following surgery. Persistent POCD is most commonly experienced by older individuals and is associated with a greater vulnerability to developing Alzheimer's disease, but the underlying mechanisms are not known. It is known that laparotomy (exploratory abdominal surgery) in aged rats produces memory impairments for 4 days. Here we report that postsurgical treatment with morphine extends this deficit to at least 2 months while having no effects in the absence of surgery. Indeed, hippocampal-dependent long-term memory was impaired 2, 4, and 8 weeks postsurgery only in aged, morphine-treated rats. Short-term memory remained intact. Morphine is known to have analgesic effects via μ-opioid receptor activation and neuroinflammatory effects through Toll-like receptor 4 activation. Here we demonstrate that persistent memory deficits were mediated independently of the μ-opioid receptor, suggesting that they were evoked through a neuroinflammatory mechanism and unrelated to pain modulation. In support of this, aged, laparotomized, and morphine-treated rats exhibited increased gene expression of various proinflammatory markers (IL-1β, IL-6, TNFα, NLRP3, HMGB1, TLR2, and TLR4) in the hippocampus at the 2-week time point. Furthermore, central blockade of IL-1β signaling with the specific IL-1 receptor antagonist (IL-1RA), at the time of surgery, completely prevented the memory impairment. Finally, synaptophysin and PSD95 gene expression were significantly dysregulated in the hippocampus of aged, laparotomized, morphine-treated rats, suggesting that impaired synaptic structure and/or function may play a key role in this persistent deficit. This instance of long-term memory impairment following surgery closely mirrors the timeline of persistent POCD in humans and may be useful for future treatment discoveries.
AB - Postoperative cognitive dysfunction (POCD) is the collection of cognitive impairments, lasting days to months, experienced by individuals following surgery. Persistent POCD is most commonly experienced by older individuals and is associated with a greater vulnerability to developing Alzheimer's disease, but the underlying mechanisms are not known. It is known that laparotomy (exploratory abdominal surgery) in aged rats produces memory impairments for 4 days. Here we report that postsurgical treatment with morphine extends this deficit to at least 2 months while having no effects in the absence of surgery. Indeed, hippocampal-dependent long-term memory was impaired 2, 4, and 8 weeks postsurgery only in aged, morphine-treated rats. Short-term memory remained intact. Morphine is known to have analgesic effects via μ-opioid receptor activation and neuroinflammatory effects through Toll-like receptor 4 activation. Here we demonstrate that persistent memory deficits were mediated independently of the μ-opioid receptor, suggesting that they were evoked through a neuroinflammatory mechanism and unrelated to pain modulation. In support of this, aged, laparotomized, and morphine-treated rats exhibited increased gene expression of various proinflammatory markers (IL-1β, IL-6, TNFα, NLRP3, HMGB1, TLR2, and TLR4) in the hippocampus at the 2-week time point. Furthermore, central blockade of IL-1β signaling with the specific IL-1 receptor antagonist (IL-1RA), at the time of surgery, completely prevented the memory impairment. Finally, synaptophysin and PSD95 gene expression were significantly dysregulated in the hippocampus of aged, laparotomized, morphine-treated rats, suggesting that impaired synaptic structure and/or function may play a key role in this persistent deficit. This instance of long-term memory impairment following surgery closely mirrors the timeline of persistent POCD in humans and may be useful for future treatment discoveries.
KW - Aging
KW - Alzheimer's disease
KW - Cognitive impairment
KW - Hippocampus
KW - Morphine
KW - Neuroinflammation
KW - Opioids
KW - Surgery
KW - Synaptic dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85097862887&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097862887&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2020.11.008
DO - 10.1016/j.neurobiolaging.2020.11.008
M3 - Article
C2 - 33341652
AN - SCOPUS:85097862887
SN - 0197-4580
VL - 98
SP - 214
EP - 224
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -