Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats

Highlights

• Surgery and morphine-induced memory deficits lasting 8 weeks in aged, but not young rats.

• Morphine-induced POCD in aged rats occurred independently of opioid receptors.

• Morphine-induced POCD was associated with increased hippocampal proinflammatory markers.

• IL-1RA pretreatment prevented morphine-induced POCD in aged rats.

• Morphine-induced POCD was associated with dysregulated hippocampal synaptic markers.

Abstract

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.

Introduction

Postoperative cognitive dysfunction (POCD) is the constellation of cognitive symptoms, lasting anywhere from days to months, that many surgical patients experience immediately following a variety of surgical procedures (e.g., abdominal, orthopedic, and cardiac surgeries). These symptoms range from slight confusion to difficulties with executive functions, an inability to form long-term episodic memories, to Alzheimer’s disease (AD) and other dementias (Bedford, 1955; Ramaiah and Lam, 2009; Rundshagen, 2014; Terrando et al., 2011). Many POCD cases are transient, but importantly, long-lasting cases of POCD are more likely to develop into AD (Bickel et al., 2008; McCusker et al., 2001; Wacker et al., 2006) and are thus, more devastating. Advanced age is known to be the strongest risk factor for this persistent form of POCD (Moller et al., 1998; Monk and Price, 2011), but preclinical research examining cognitive function following a surgical procedure, even in aged subjects, has failed to recapitulate this persistent form of POCD typically finding only relatively brief deficits, on the order of days (Barrientos et al., 2012; Rosczyk et al., 2008; Wan et al., 2010; Wang et al., 2020).

In aging, microglial priming has been identified as a key mediator of exaggerated neuroinflammation, primarily in the hippocampus, following a variety of peripheral insults, including surgery (Barrientos et al., 2015a; Cunningham et al., 2005; Norden et al., 2015). Exaggerated neuroinflammation can result in deteriorated cellular and molecular processes important for forming memories, which, in turn, causes precipitous long-term memory deficits (Abraham et al., 2008; Barrientos et al., 2006, 2009, 2012; Chapman et al., 2010; Cunningham et al., 2005; Frank et al., 2010b; Godbout et al., 2005; Griffin et al., 2006; Hauss-Wegrzyniak et al., 2002; Spencer et al., 2017; Tanaka et al., 2018). Thus, it is not surprising that previous preclinical POCD studies, including our own, have demonstrated a causal role for proinflammatory cytokines in surgery-induced cognitive impairments. However, as noted above, none of these works have found impairments lasting beyond 1 to 7 days postsurgery (Barrientos et al., 2012; Rosczyk et al., 2008; Wan et al., 2010; Wang et al., 2020). Therefore, it is unknown whether similar mechanisms underlie persistent forms of POCD, and whether interventions shown to ameliorate these short-lived impairments would be effective in long-lasting cases.

One potential risk factor surrounding the perioperative setting that has been overlooked in rodent models of POCD thus far is the prevalent use of opioid analgesics among postsurgical patients. Indeed, about 90% of patients are prescribed morphine and other opioids for postsurgical pain management (Aubrun et al., 2012; Garimella and Cellini, 2013) owing to their potent analgesic effects mediated by activation of the μ-opioid receptor (Corder et al., 2018). Importantly, a growing preclinical literature has independently shown that morphine and other opioids are capable of triggering a robust neuroinflammatory response through activation of the pattern recognition receptor Toll-like receptor 4 (TLR4), which, paradoxical to its prescribed purpose, prolongs neuropathic and postsurgical pain (Grace et al., 2016, 2019; Hutchinson et al., 2007, 2010a; Johnson et al., 2014; Wang et al., 2012; Zhang et al., 2018). Interestingly, aging rodents exhibit significantly increased TLR4 expression in the hippocampus compared to younger rats (Fonken et al., 2016), and activation of these receptors (with a peripheral E. coli infection) has resulted in exaggerated neuroinflammatory responses and memory impairments (Barrientos et al., 2009, 2015b; Fonken et al., 2016; Frank et al., 2010a). Therefore, we explored whether the combination of aging, surgery, and morphine treatment might cause a synergistic neuroinflammatory response strong enough to cause persistent POCD. If so, this would have implications for the use of opioid analgesic postsurgery in aging humans. We administered a 7-day regimen of morphine following laparotomy in young adult and aged rats and measured hippocampally mediated memory at several time points to determine whether the combination of these factors would produce persistent memory impairments. Furthermore, we investigated mechanisms by which these factors might extend POCD symptoms in aging.