Experimental Neurology 360 (2023) 114287

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Experimental Neurology
journal homepage: www.elsevier.com/locate/yexnr

Research paper

Chronic pain in Alzheimer’s disease: Endocannabinoid system

Henry Blanton a, P. Hemachandra Reddy a, b, Khalid Benamar a, *
a
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX 79430, USA
b
Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in
Pain mobility and daily activities, dependence on opioids, anxiety, depression, sleep deprivation, and reduced quality
Endocannabinoid of life. Alzheimer’s disease (AD), a devastating neurodegenerative disorder (characterized by a progressive
Alzheimer
impairment of cognitive functions) in the elderly, is often co-morbid with chronic pain. AD is one of the most
Aging
common neurodegenerative disorders in the aged population. The reported prevalence of chronic pain is 45.8%
of the 50 million people with AD. As the population ages, the number of older people who experience AD and
chronic pain will also increase. The current treatment options for chronic pain are limited, often ineffective, and
have associated side effects. This review summarizes the role of the endocannabinoid system in pain, its potential
role in chronic pain in AD, and addresses gaps and future directions.

1. Introduction hyperphosphorylated tau.

Pain is a complex phenomenon that comprises sensory, affective, and
cognitive components. Pain is defined as an unpleasant sensory and
emotional experience associated with or resembling that associated with
actual or potential tissue damage. (IASP, 2020). Chronic pain is defined
as pain persisting beyond three months. It is a significant healthcare
burden affecting approximately 50 million adults in the US alone
(Dahlhamer et al., 2018), with an estimated annual healthcare burden of
$600 billion in the United States alone (Gaskin and Richard, 2012).
Chronic pain, one of the most common reasons adults seek medical care,
has been linked to restrictions in mobility and daily activities, depen­
dence on opioids, anxiety, depression, sleep deprivation, and reduced
quality of life.
Alzheimer’s disease (AD) is the most common form of dementia,
accounting for 60–80% of dementia cases (Association, A. S., 2021). In
2020, the estimated cost of caring for and treating people with Alz­
heimer’s disease was $305 billion. By 2050, these costs are projected to
be more than $1.1 trillion. (CDC, 2020) AD is a devastating neurode­
generative disorder and one of the most common causes of neurode­
generative dementia in the elderly, and adults over 65 comprise
approximately 95% of AD cases (Zhu et al., 2015). It is characterized by
a progressive impairment of cognitive functions. AD is characterized
pathologically by extracellular amyloid β (Aβ) plaques and intracellular
neurofibrillary tangles (NFTs) composed of abnormally
Among the aging population, cognitive decline, and chronic pain are
two significant healthcare burdens affecting the aging population and
the healthcare systems and caregivers that support these individuals.
(van Kooten et al., 2017). The reported prevalence of chronic pain in AD
patients is 45.8% of the 50 million people worldwide (van Kooten et al.,
2016).
This review will provide a brief overview of chronic pain in aging
with and without AD, shared pathology and mechanisms seen in older
adults with AD and chronic pain, and explore the therapeutic potential
of drugs targeting the endocannabinoid system as a novel treatment
avenue.
2. Age, AD, and pain
In 2020, the population aged 60 years and overreach 1.4 billion.
(WHO, 2021) By 2050, the world’s population of people aged 60 years
and older will double (2.1 billion). (WHO, 2021) In the United States,
the population of older individuals (age 65+) is projected to double in
the coming decades, from 49 million in 2016 to 99 million in 2060
(Vespa et al., 2018). Chronic pain in the elderly is a growing concern as
the world’s population ages (Domenichiello and Ramsden, 2019).
Indeed, old age (age 65+) is significantly correlated with an increased
incidence of chronic pain conditions (Dahlhamer et al., 2018; Yang and
Chang, 2019), The most common forms of chronic pain among older

* Corresponding author.
E-mail address: khalid.benamar@ttuhsc.edu (K. Benamar).

https://doi.org/10.1016/j.expneurol.2022.114287
Received 8 August 2022; Received in revised form 9 November 2022; Accepted 23 November 2022
Available online 29 November 2022
0014-4886/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
H. Blanton et al.
adults affect the back, neck, and joints (Husky et al., 2018; Guez et al.,
2002; Pleis et al., 2009). Despite the increased prevalence of chronic
pain in the elderly, some studies have found increased pain thresholds to
experimentally induced pain in older adults (Lautenbacher et al., 2017),
while other studies show mixed effects in pain thresholds between
younger versus older adults (El Tumi et al., 2017). Differences in pain
progression, ages, gender, sample size, modalities of evoked pain, in­
tensity, and outcome measures used may account for the discrepancy.
AD is associated with increased chronic pain prevalence (van Kooten
et al., 2016). Similarly showing varied responses to experimental pain
thresholds, including increased sensitivity (van Kooten et al., 2016;
Kunz et al., 2009; Kunz et al., 2007; Jensen-Dahm et al., 2014; Beach
et al., 2015; Beach et al., 2016) and decreased sensitivity (Benedetti
et al., 1999; Gibson et al., 2001; Monroe et al., 2017), which may vary
based on the type of painful stimuli and its intensity. The most longi­
tudinal studies of pain in people with dementia revealed that at the time
of diagnosis, individuals with dementia reported significantly more pain
than individuals without dementia. (Kumaradev et al., 2021). Pain
prevalence and the increase in its intensity are of particular concern.
Currently, a considerable proportion of people with AD and chronic pain
likely may not be receiving adequate treatment compared to those
without AD. Additionally, pain is a key trigger for behavioral and psy­
chological symptoms of dementia (Atee et al., 2021; Flo et al., 2014)
such as agitation and mood disorders, and poorly managed pain in AD
can result in overprescribing harmful antipsychotic medications. Addi­
tionally, inadequately treated chronic pain can lead to restrictions on
daily activity and psychological problems, including depression and
anxiety.
Below we summarized some potential mechanisms that may account
for the enhanced pain in AD.
3. AD and chronic pain: shared disease features
3.1. Brain structures
Given that AD is a brain disease, there is a concern that AD may affect
some brain areas involved in pain and, therefore, pain response and the
effect of analgesics. AD produces structural and functional brain alter­
ations, including changes in gray matter volume and disrupted func­
tional connectivity between brain networks (Palesi et al., 2016). Among
the areas disrupted by AD are brain areas critical for processing pain
information (Lawn et al., 2021). Among the earliest sites affected by AD
are the basal forebrain and medial temporal lobes, areas involved in pain
processing, while the sensory cortices responsible for pain perception
remain intact (Lawn et al., 2021).
Neuroimaging studies showed that when exposed to experimental
pain, subjects with early-stage AD had sustained activity in pain pro­
cessing regions such as the dorsolateral prefrontal cortex (dlPFC), sug­
gesting AD patients may have greater difficulty in the cognitive and
emotional appraisal of pain, and pain may be more distressing (Cole
et al., 2006). Similarly, fMRI analysis of networks in experimental pain
reveals greater activation of Salience and Default Mode Networks in AD
patients compared to healthy controls, which may correlate to greater
attention to pain, and increased emotional responsiveness to pain
(Beach et al., 2017). In addition to the brain structure changes, other
shared features between AD and chronic pain include neuro­
inflammation and mitochondria dysfunction.
3.2. Neuroinflammation
Neuroinflammation is a term used to describe the broad range of
immune responses of the central nervous system (Lyman et al., 2014).
Four features of neuroinflammation include increased vascular perme­
ability, leukocyte infiltration, glial cell activation, and increased pro­
duction of inflammatory mediators such as cytokines and chemokines
(Ji et al., 2014). Mechanistically, neuroinflammation drives widespread
2
Experimental Neurology 360 (2023) 114287
chronic pain via central sensitization, which can be induced and main­
tained by cytokines, chemokines, and other glia-produced mediators.
Neuroinflammation has a key role in the induction and maintenance of
chronic pain (Ji et al., 2014; Ellis and Bennett, 2013; White et al., 2005),
(Ji et al., 2018).
Neuroinflammation not only serves as a driving force for chronic
pain but is also implicated in neurodegenerative diseases such as AD
(Heneka et al., 2015). Clinical (Hamelin et al., 2016; Fan et al., 2017;
Zhou et al., 2021; Leng and Edison, 2021) and preclinical (Martin et al.,
2017) data have shown neuroinflammation in the brains with AD. In AD,
neuroinflammation, instead of being a mere bystander activated by
emerging senile plaques and neurofibrillary tangles, contributes as much
to the pathogenesis as the plaques and tangles themselves (Heneka et al.,
2015; Zhang et al., 2013). In AD, microglia can bind to soluble Aβ
oligomers and Aβ fibrils, which are thought to be part of the inflam­
matory reaction in AD (Heneka et al., 2015). Studies showed that
microglial activation contributes to Tau pathology during AD patho­
genesis (Hopp et al., 2018; Asai et al., 2015; Maphis et al., 2015; Bhaskar
et al., 2010).
3.3. Mitochondria
Mitochondria play a critical role in ATP synthesis, redox balance, and
many other biological processes, including ion homeostasis, nuclear
gene expression, protein turnover, and post-translational modification
and apoptosis (Bozi et al., 2020). In terms of pain, both neuropathic and
chronic inflammatory pain models have been associated with neuronal
mitochondrial dysfunction, including impaired bioenergetics, calcium
overload, oxidative stress, and aldehydic burden (Zambelli et al., 2014;
Flatters, 2015).
Many lines of evidence suggest that mitochondria have a central role
in aging-related neurodegenerative diseases (Lin and Beal, 2006).
Abnormal mitochondrial dynamics have been found to be early events in
the AD disease process in studies using post-mortem AD brains, AD cell
cultures, and AD mouse models (Reddy and McWeeney, 2006; Reddy
et al., 2005; Manczak et al., 2011; Manczak and Reddy, 2012a; Kandi­
malla et al., 2016; Manczak et al., 2016; Manczak et al., 2018; Reddy
et al., 2018). Increased mitochondria fission and reduced fusion can
impair mitochondrial dynamics in AD-affected neurons (Manczak et al.,
2019; Manczak and Reddy, 2012b; Knott and Bossy-Wetzel, 2008).
Other studies using AD neurons revealed that Aβ interacts with The
dynamin-related protein (Drp1), with a subsequent increase in free
radical production, which in turn activates Drp1 and Mitochondrial
fission protein 1 (Fis1), causing excessive mitochondrial fragmentation,
defective transport of mitochondria to synapses, provides low synaptic
ATP and ultimately leads to synaptic dysfunction (Morton et al., 2021).
Further studies revealed that phosphorylated tau (p-tau) interacts with
Drp1, enhances GTPase Drp1 enzymatic activity, and leads to excessive
fragmentation of mitochondria and mitochondrial dysfunction in AD.
Substantial amounts of data have demonstrated mitochondrial
dysfunction in chronic pain (Bozi et al., 2020; Flatters, 2015; Doyle and
Salvemini, 2021; Hernandez-Beltran et al., 2013; Lagos-Rodriguez et al.,
2020).
Taken together, there is a significant overlap in AD and chronic pain
and shared mechanisms summarized in Fig. 1 that may account for the
enhanced pain in AD.
While the current treatment options for chronic pain are limited,
often ineffective, and have associated side effects, the simultaneous
presence of chronic pain and AD could pose an additional challenge in
managing chronic pain (please see section 3). In Fig. 2, we summarize
the potential mechanism(s) by which pain sensitivity is increased in AD
with chronic pain.
Based on this background (section 3), it is unlikely to assume that
pain response and analgesic efficacy are the same in older adults with
AD versus non-AD. Therefore, chronic pain management in the aged
population needs to be addressed with and without AD. This will ensure
H. Blanton et al.
Fig. 1. Chronic pain and AD: commons disease features.
Fig. 2. Potential mechanism(s) by which pain severity is increased in AD.
that 45.8% of the 50 million people worldwide (van Kooten et al., 2016)
with chronic pain and AD are receiving adequate treatment compared to
those without AD.
In the next section, we will explore the endocannabinoid system’s
role in pain and AD.
4. The endocannabinoid system’s role in pain and AD
4.1. The cannabinoids and endocannabinoid System
The endocannabinoid system serves as a broadly acting modulatory
system, influencing various processes in the body, with key roles in in­
flammatory processes and pain modulation. The endocannabinoid sys­
tem at its core is defined by three main components: 1) the endogenous
receptors, 2) the ligands for those receptors known as endocannabi­
noids, and 3) the enzymes responsible for the synthesis and degradation
of those endocannabinoids. The two primary cannabinoid receptors, the
CB1 and CB2 receptors are G-protein coupled receptors (GPCR) (Felder
et al., 1995; Glass and Northup, 1999).
Activation of cannabinoid receptors produces an inhibitory effect on
cell activity via multiple signaling pathways, including inhibition of
adenylyl cyclase-mediated cAMP formation and modulation of potas­
sium and calcium channels (Felder et al., 1995). CB1 is expressed
throughout the central and peripheral nervous systems, and CB1 acti­
vation on CNS neurons is responsible for the psychoactive effects asso­
ciated with delta-9-tetrahydrocannabinol (Δ-9-THC), the primary
psychoactive component in Cannabis sativa (Devane et al., 1992). In
contrast, CB2 shows low expression in CNS neurons under normal
conditions but is highly expressed in immune cells and peripheral tissues
(Matsuda et al., 1990; Munro et al., 1993).
The ligands acting on these receptors, known as endocannabinoids,
are fatty acid derivatives synthesized on demand and acting in a retro­
grade manner (Wilson and Nicoll, 2001). The two best-characterized
endocannabinoids are 2-arachidonoylglycerol (2-AG) and 2-arachido­
noylethanolamide, also known as Anandamide (AEA) (Devane et al.,
1992; Mechoulam et al., 1995).
Levels of these endogenous cannabinoids may be elevated to produce
therapeutic effects through the use of inhibitors of the enzymes
responsible for their degradation, monoacylglycerol lipase (MAGL) for
2-AG, and fatty acid amide hydrolase (FAAH) for AEA (Cravatt et al.,
3
Experimental Neurology 360 (2023) 114287
1996; Dinh et al., 2002).
4.2. The endocannabinoid system and pain
The endocannabinoid system is expressed throughout pain pathways
in the CNS, PNS, and neuroimmune system, and cannabinoids have
shown beneficial effects in various preclinical models of acute and
chronic pain of mixed origins (Finn et al., 2021). Cannabinoids may
produce analgesic effects through inhibition of pain signaling at the
periphery, spinal cord, and brain by either dampening the ascending
nociceptive information that initiates the process of pain or producing
descending modulation of pain. In the periphery, evidence for inhibition
of ascending nociceptive signaling by cannabinoids has been demon­
strated via local administration routes such as intraplantar injection.
Indeed, in animal pain models, local administration of cannabinoids has
been demonstrated to be antinociceptive via both CB1 and CB2 re­
ceptors. (Calignano et al., 1998)
In the brain, CB1 receptor agonists (e.g., Δ9-THC, CP 55,940, WIN
55,212–2) activate descending (inhibitory) pain circuits in multiple
pain-modulatory regions, including the amygdala (Manning et al.,
2003), periaqueductal gray (Lichtman et al., 1996) and rostral ventro­
medial medulla (Martin et al., 1998). Cannabinoids may also relieve
pain through their anti-inflammatory effects via CB1, CB2, and other
receptors. Selective CB2 receptor agonists show analgesic efficacy in
animal inflammatory and neuropathic pain models by inhibiting pro-
inflammatory signaling (Malanjr et al., 2003). Additionally, orphan
GPCRs such as GPR55 and GPR18 have also been implicated as targets
for cannabinoid-mediated antinociception (Armin et al., 2021; Nar­
asimhan et al., 2020).
4.3. The endocannabinoid system in AD and AD mouse models
The endocannabinoid system has been demonstrated to be altered in
AD, and these changes may reflect potential druggable targets to relieve
symptomology and alter disease progression. Post-mortem analyses of
the frontal cortex from AD patients found a decrease in CB1 expression,
an increase in protein nitration of CB1 and CB2—thought to reflect
oxidative damage, as well as a decrease in G-protein coupling at the CB1
receptor produced by the agonist 3HWIN55,212–2 (Ramirez et al.,
2005). The CB2 receptor was found to be upregulated in activated
H. Blanton et al.
microglia in neuritic plaques in the parahippocampal cortex, in addition
to an increase in FAAH protein levels and activity in plaque-associated
astrocytes (Benito et al., 2003). Endocannabinoid levels have also
been found to be altered in AD patients. Post-mortem studies of AD
brains found an increase in the 2-AG synthesizing and degradative en­
zymes, DAGL and MAGL, in the hippocampus (Mulder et al., 2011), and
the prefrontal and temporal cortex, lower levels of anandamide were
found, which correlated to an increase in amyloid beta (Aβ) levels (Ju
et al., 2014).
Exogenous cannabinoids have shown beneficial effects in AD models,
improving behavioral symptoms through improved clearance of plaques
and decreasing neuroinflammation (Abate et al., 2021). In addition,
centrally acting CB1 receptor agonists have shown beneficial effects in
preclinical AD studies, reducing the accumulation of Aβ (Cao et al.,
2014; Janefjord et al., 2014), inhibiting neuroinflammation (Currais
et al., 2016; Schubert et al., 2019), and improving cognition (Aso et al.,
2016). However, centrally acting CB1 agonists have known downsides;
their ability to impair learning and memory is particularly relevant to
AD. Impairments of CB1 agonists in memory are attributed to the high
density of CB1 receptors in the hippocampus (Lichtman et al., 1995;
Clarke et al., 2008; Kosiorek et al., 2003). Indeed, in the hippocampus,
CB1 agonists may reduce long-term potentiation (Terranova et al., 1995;
Hill et al., 2004), alter firing patterns (Robinson et al., 2007; Goona­
wardena et al., 2011; Barbieri et al., 2016), and decrease acetylcholine
release (Gessa et al., 1997; Braida and Sala, 2000). It is possible, how­
ever, that some of these adverse effects are a function of dose and
perhaps age that can be avoided. Indeed, in old mice, Δ9THC has been
found to have beneficial effects on memory when administered in low
doses (Aso et al., 2016; Bilkei-Gorzo et al., 2017; Sarne et al., 2018).
CB2 receptor expression has been found to be increased in the post-
mortem brains of AD patients (Benito et al., 2003; Grunblatt et al.,
2007), while preclinical studies have shown increased CB2 receptor
expression in the brain and spinal cord in states of chronic pain and
inflammation (Hsieh et al., 2011; Ghosh et al., 2022). The potential role
of CB2 receptors as therapeutic targets in AD models has been explored
limitedly but with promising results. For example, selective targeting of
CB2 receptors with the agonist JWH133 improved cognitive perfor­
mance, decreased microglial reactivity, and reduced inflammatory cy­
tokines (Aso et al., 2013). Additionally, in rats injected in the
hippocampus with Aβ, selective targeting of CB2 has been shown to
improve cognitive performance by improving Aβ clearance (Wu et al.,
2013). Moreover, genetic knockout of the CB2 receptor has been found
to increase Aβ42 and plaque deposition and increase plaque-associated
microglia in the J20 APP AD mouse model (Koppel et al., 2013). Thus,
CB2 could be a target to slow or reverse AD pathology and improve
cognition.
5. Potential therapeutic role of cannabinoids in older adults
with AD and chronic pain
Older adults also comprise one of the fastest-growing age groups
using cannabis and cannabinoids for medical purposes (Han and Pala­
mar, 2020). Among older adults using cannabis/cannabinoids for
medical purposes, relief from chronic pain is overwhelmingly reported
as a primary reason for use (Reynolds et al., 2018; Yang et al., 2021).
Currently, there is no direct information about the use of cannabis/
cannabinoids for the treatment of chronic pain in older individuals with
AD. However, there is some evidence showing that the endocannabinoid
system may still function in AD and thus has the potential to be a target
for therapeutic strategy. For example, the beneficial effects of cannabis/
cannabinoids on the physiological, behavioral, and neuropsychiatric
symptoms associated with AD have been reported. In particular, in in­
dividuals with AD, decreased agitation was seen in studies investigating
the effects of dronabinol (Volicer et al., 1997), nabilone (Herrmann
et al., 2019), and Δ9THC-containing cannabis oil (Shelef et al., 2016).
Sleep disturbances are also prevalent in AD, where a bidirectional
4
Experimental Neurology 360 (2023) 114287
relationship has been proposed between worsening sleep quality and
worsening AD symptomatology (Ju et al., 2014; Guarnieri and Sorbi,
2015; Villa et al., 2015). In AD patients, Δ9THC-containing cannabis oil
(Shelef et al., 2016) and dronabinol (Walther et al., 2006) have shown
beneficial effects on sleep in addition to decreasing agitation and
improving mood.
6. Conclusions, gaps, and future directions
The reported prevalence of chronic pain is 45.8% of the 50 million
people with AD worldwide. (van Kooten et al., 2016) Pain may be
underestimated in AD patients as they may be unable to communicate
their pain, (Achterberg et al., 2013) particularly in more severe stages of
dementia. As the population ages, the number of older people who
experience AD and pain will also increase (Prince et al., 2013). The
current treatment options for chronic pain are limited, often ineffective,
and have associated side effects. Despite rapidly shifting policies
affecting access to cannabinoids, the use of cannabis continues to in­
crease among older adults nationally (Han and Palamar, 2020) and the
high prevalence of chronic pain in AD (van Kooten et al., 2016). To date,
there are no data on whether and how the endocannabinoid system is
regulated in individuals with AD who have chronic pain. Therefore,
there is an urgent need to address these knowledge gaps.
Author contribution
All authors equally contributed to the conception and writing of the
article.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to.
Data availability
The data that has been used is confidential.
Acknowledgements
This work was supported by grants DA053824-02S1 and DA053824
from NIH.
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