A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review
A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review
0 S. D. Skaper Department of Pharmacology, University of Padova , Padua , Italy
1 M. Fusco Center for Medical Documentation and Information , Epitech, Padua , Italy
2 G. Varrassi (&) A. Paladini Department of Anesthesia and Pain Medicine, University of L'Aquila , L'Aquila , Italy
3 M. C. Pace Department of Anesthesia and Pain Medicine, University of Napoli , Naples , Italy
4 S. Coaccioli Department of Internal Medicine, University of Perugia , Terni , Italy
5 P. Zis Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield , UK
6 D. Battelli Department of Anesthesia and Pain Medicine, San Marino Hospital , San Marino , San Marino
Chronic pain is an important health and social problem. Misuse and abuse of opioids in chronic non-cancer pain management seem to be a huge problem, in some countries. This
Chronic pain; Opioid abuse; Opioid induced hyperalgesia; Opioid induced tolerance; Opioid misuse; PEA
could probably affect the normal use of such
analgesics in patients in need of them. Basic and
clinical researches should find the solution to
mitigate the potential damage. Dysregulation of
mast cell and microglia activation plays an
important role in the pathogenesis and
management of chronic pain. Persistent mast cell
activation sensitizes nociceptors and initiates
central nervous system inflammatory processes,
involving microglial cell activation and
sensitization of spinal somatosensory neurons.
Exposure of mast cells and microglia to opioids is
well known to provoke activation of these
nonneuronal immune cell populations, thereby
contributing to an exacerbation of
pro-inflammatory and pro-nociceptive processes and
promoting, over the long-term, opioid-induced
hyperalgesia and tolerance. This review is
intended to provide the reader with an overview
of the role for these non-neuronal cells in
opioid-induced chronic pain and tolerance as a
consequence of prolonged exposure to these
drugs. In addition, we will examine a potential
strategy with the aim to modulate
opioid-induced over-activation of glia and mast cells,
based on endogenous defense mechanisms and
fatty acid amide signaling molecules.
Chronic pain affects an estimated 20% of the
world’s population and accounts for nearly
onefifth of physician visits. Pain is classified as
‘‘chronic’’ when it lasts beyond the normal
healing time and persists or recurs for longer
than 3 months. It is well distinguished from the
acute warning function of the physiological
nociception. Such pain often becomes the sole
or predominant clinical problem in some
]. For many years, it has been
accepted as ‘‘a disease in its own right’’ [
]. Its burden
on patients, on health care systems and on
society has been clearly demonstrated [
efficacious management of such a disease is still
the topic of many discussions, especially due to
its multifactorial origins.
Over the past 3 decades, following the
recommendations of the WHO guideline [
use of opioids has been widely accepted for the
treatment of cancer pain. In the last 2 decades,
the simple and appealing ‘‘analgesic ladder’’
suggested in the WHO document has been too
simplistically interpreted and has been
increasingly applied also to patients with chronic
noncancer pain, as well as those with cancer [
This was apparently useful for the patients,
because it was supposed to be of benefit in most
of the chronic pain patients. Although the
longterm benefit of opioid analgesia was anecdotally
accepted, formal empirical evidence of such was
never generated. Unfortunately, as in many
other aspects of the chronic pain therapy, there
are side effects and complications. The
subsequent large increase in prescribing opioids,
particularly in the United States, resulted in
what has been identified as an ‘‘opioid
epidemic’’, with the consequent harm of misuse
and abuse of this class of drugs [
Regardless, chronic pain remains a major
source of suffering and represents a global
health priority calling for special attention and
care. Even though considerable progress has
been made in the classification and
identification of pathophysiologic mechanisms of
chronic pain, translating this knowledge into
the development of an effective pain
management or of improved analgesic medications
specifically for chronic pain remains a
challenge. At this point, a brief digression on the
role of inflammation and non-neuronal cells in
chronic pain states is in order. Moreover, the
American claim for potential danger of the
chronic opioid use has stimulated the authors
to review the recent literature, in the hope to
make clear the pathophysiology and the
potentialities to prevent some of the
phenomena consequent to such use. This article is based
on previously published data and does not
contain studies with human participants or
animals performed by any of the authors.
CHRONIC PAIN: THE ROLE
OF INFLAMMATION AND NON
Inflammation is a natural reaction of
self-protection to remove harmful stimuli [
] and is an
integral component of the immune response. At
the same time, there are occasions when the
inflammatory response itself damages host
tissue and causes organ dysfunction. For example,
this occurs when there is an overly robust acute
or subacute inflammatory response to
pathogens or debris from damaged host cells [
their review, Nathan and Ding [
] clearly note
that the fundamental problem regarding
inflammation is not how often it starts, but how
often it fails to subside. Undoubtedly, that
nonresolving inflammation is one of the principal
contributors to the medical burden in
industrialized societies. Inflammation is particularly
insidious in cases in which the peripheral and
central nervous systems are involved
(‘neuroinflammation’), playing an important role in
the pathogenesis of chronic pain [
], as well as
chronic neurodegenerative diseases [
neuropsychiatric illness [
One of the cardinal advances in the
neurosciences over the past few decades has been the
discovery of an extensive bi-directional
communication between the immune system and
the central nervous system (CNS).
Pro-inflammatory cytokines occupy a key position by
regulating host responses to infection,
inflammation, stress and trauma. Principal players in
these actions are glia (astrocytes and microglia),
and mast cells. These cell populations
constitute important sources of inflammatory
mediators and may have significant roles in
conditions ranging from chronic pain to
neurodegenerative diseases and neuropsychiatric
]. This analysis will discuss
the role of non-neuronal cells in chronic pain,
their dysregulation in response to long-term
exposure to opioids, followed by the
consideration of a strategy to modulate opioid-induced
over-activation of glia and mast cells, based on
endogenous defense mechanisms and fatty acid
amide signaling molecules.
Neuropathic pain results from damage and/
or degeneration of the sensory nervous system.
Central neuropathic pain accompanies spinal
cord injury, multiple sclerosis, and in certain
cases strokes; while painful peripheral
neuropathies frequently occur with diabetes and
other metabolic or infectious conditions.
Neuropathic pain can also be a direct result of
cancer involving peripheral nerves or as a side effect
of chemotherapy. The triggering and
maintenance of neuropathic pain states depends on
Schwann cells, spinal microglia and astrocytes,
together with elements of the peripheral
immune system [
]. Under pathological
conditions, dorsal horn microglia become activated
with up-regulation of purinergic
] that participate in neuropathic pain
Upon degranulation, mast cells release
molecules which activate or sensitize
nociceptors, thereby contributing directly to
neuropathic pain [
]. Peripheral nerve mast cells
constitute the first line of activation at the site
of damage, and promote the recruitment of
neutrophils and macrophages [
Degranulation of mast cells also activates
trigemino-cervical and lumbosacral pain pathways to elicit
widespread tactile pain hypersensitivity [
possibly mediated by a sensitizing effect of
histamines on nociceptors. Further, the rapid
release of nerve growth factor (NGF) by mast
cells can sensitize nociceptors by engaging the
latter’s high-affinity TrkA receptors (and
indirectly via other peripheral cell types) [
cells are important mediators of chronic visceral
pain, as well [
INTERACTION BETWEEN NON
NEURONAL CELLS AND OPIOIDS:
A PAINFUL ENCOUNTER
For many chronic pain conditions, the medical
community has responded with long-term use
of analgesics that were originally developed for
acute pain. Among these are the opioids, which
comprise natural, semi-synthetic or synthetic
analgesic molecules with a pharmacological
action similar to opium and endogenous
endorphins. In particular, the suggestion of the
WHO analgesic ladder, which legitimized the
use of opioids to treat severe pain in terminally
ill cancer patients, also encouraged application
of the same therapeutic approach for chronic
non-cancer pain, without fostering the search
for solutions to limit opioids’ adverse
]. Long-term use of opioids is
accompanied by decreasing levels of analgesic
response not readily attributable to advancing
underlying disease, necessitating dose
escalation to manage pain (‘tolerance’). The latter
manifestation, along with other adverse events
caused by escalating doses (e.g., over-sedation,
respiratory depression, abuse potential) often
leaves the patient unable to continue analgesic
therapy—significantly diminishing quality of
life in those with chronic pain [
recent criticisms regarding the growing climate
of opiophobia and oligoanalgesia [
], such as
in the United States, the use of opioids had
devolved to the point of becoming an epidemic
of abuse [
To bring attention to this situation, the
American Academy of Neurology recently
published a position paper in the journal Neurology
with its recommendations on the prescription
of these drugs, defining the emergency as ‘‘an
epidemic of public health’’ [
]. This represented
a response to publication of the results reported
by a commission of experts, appointed by the
US National Institutes of Health, tasked with
assessing scientific evidence for the efficacy and
risks of opioid analgesics. Their findings
highlighted the inadequacy of most studies used to
justify the prescription of opioids—which have
been judged to be definitive neither in terms of
chronic treatment efficacy nor safety [
Not surprisingly, the Academy warned that risks
outweigh benefits when opioids are prescribed
The most frequently reported adverse events
of opioids use include constipation, nausea,
vomiting, dizziness, and drowsiness. Over the
longer term, and of a more serious nature, are
inhibition of sex hormone production,
hypogonadism, infertility, falls and fractures in older
adults, cardiac problems such as QT syndrome
(elongation interval between the Q and T waves
on the electrocardiogram), and sleep-related
breathing problems [
In addition to the development of
dependence and tolerance, opioid use can
paradoxically lead to hyperalgesia [
]. The mechanism
underlying this last effect causes us to consider
once again the involvement of non-neuronal
cells. Opioids act primarily on neuronal circuits
of the brain and spinal cord. Reciprocal
signaling between immunocompetent cells in the
periphery and the CNS (mast cells, microglia
and astrocytes cells) is a key phenomenon
underpinning chronic pain mechanisms [
By releasing potent pro-inflammatory agents,
these non-neuronal cells participate in
sensitization of neurons both in the periphery and the
CNS and the resultant chronicity
(non-resolving nature) of pain. This concept has important
implications when discussing strategies for
pharmacologically targeting chronic pain and
the use of opioids. A key point in this context is
that opioids such as morphine have direct
effects on non-neuronal cells, in particular,
mast cells and microglia. Morphine, codeine
and other opioids dose-dependently activate
and induce degranulation of mast cells [
Mast cells release numerous mediators,
including pro-inflammatory cytokines (e.g.,
interleukin-1 and tumor necrosis factor),
neuropeptides such as substance P (SP) and
proteolytic enzymes such as tryptase, which can
have multiple consequences on tissues affected
by pain. For example, tryptase and SP act
directly on nerve endings by activating and
inducing further release of SP (Fig. 1)
39, 42, 43
]. By acting in an autocrine/paracrine
manner, SP further activates mast cells to
amplify mediator release and the perception
and processing of pain signals. Mast cell-derived
NGF acts both directly by promoting
nociceptive peptide release, and indirectly on
nociceptive nerve endings by altering the mechanisms
of pain, and promoting a phenotypic change in
the same endings [
42, 44, 45
]. SP and other
nociceptive neuropeptides (e.g., calcitonin
gene-related peptide), as well as tryptase and
NGF act on vascular structures, modifying their
permeability and favoring the genesis of new
blood vessels [
38, 46, 47
]. These results
demonstrate that mast cell activation induced
by morphine and other opioids contributes to
the exacerbation of pro-inflammatory and
pronociceptive processes and, in the case of cancer,
activation of angiogenesis and promotion of
tumor growth (Fig. 1).
Mast cells, while coordinators of peripheral
neuroinflammatory processes and a leading
actor in the development of the cerebral
neuroinflammation, are not the only immune cells
upon which opioids act. Microglia, the primary
resident innate immune system cell of the CNS
is also sensitive to opioids [
subjected to chronic opioid treatment assumes
an activated phenotype similar to that in
chronic and neuropathic pain [
response to chronic morphine exposure,
microglia switch from a ramified shape
characteristic of a resting state to an amoeboid form,
accompanied by up-regulation of cell surface
markers CD11b and ionized calcium-binding
35, 56, 57
]. These changes represent
the cellular and molecular signs of microglial
cell activation. Microglia express l-and k-opioid
receptors, further supporting their role as
targets for opioids (Fig. 1) [
]. Opioids may
also indirectly activate glia via a neuron-glia
signal mediated by the chemokine fractalkine
Ligand engagement of opioid receptors on
microglia leads to the release of chemokines
(e.g., chemokine ligand 2 and CXC-chemokine
ligand 1), cytokines (e.g., tumor necrosis
factora, interleukins-1b, -6 and -10) and neurotrophic
factors such as NGF and brain-derived
neurotrophic factor (BDNF), and up-regulation of
the purinergic receptors P2X4R and P2X7R and
the pattern recognition receptor Toll-like
receptor 4, all of which participate in
]. In particular, BDNF
Fig. 1 Beside neurons, opioid receptors (OR) are also
expressed on non-neuron cells, and their distribution is
altered by chronic opioid treatment. The activation of
nonneuronal cells in peripheral mast cells and spinal cord
microglia and astroglia induced by chronic opioid treatment
causes an up-regulation of membrane receptors and abnormal
released following P2X4R activation interacts
with its cognate receptor tropomyosin receptor
kinase B (TrkB) on spinal somatosensory pain
neurons which leads to down-regulation of
cotransporter 2 of potassium chloride (KCC2) and
production of pro-inflammatory cytokines and chemokines.
These events induce sensitization of peripheral and spinal
neurons, morphine tolerance and hyperalgesia, OR opioid
receptor, NK1 neurokinin 1, CGRP calcitonin gene-related
peptide, TRPV1 transient receptor potential vanilloid
receptor 1, and PAR2 protease-activated receptor 2
subsequent dysregulation of Cl- homeostasis
where primary afferent neurons interact with
second order neurons. A critical role of the
P2X4R-BDNF-KCC2 system is evident both in
opioid-induced paroxysmal hyperalgesia and in
post-neuronal injury hypersensitivity
subsequent to neuronal cell damage [
Collectively, these events contribute both to the
development of sensitization of spinal neurons
and hyperalgesia, as well as morphine tolerance
In summary, opioid analgesic action is
determined by interaction with the cognate
neuronal cell receptor, and predominates for
short-term treatment. Many of the undesirable
effects of opioids, especially hyperalgesia and
tolerance, are a consequence of opioid
interaction with receptors on non-neuronal cells,
principally mast cells and microglia. The latter
manifests initially as tolerance, with dose
escalation needed to maintain efficiency, followed
by hyperalgesia. As treatment time lengthens,
these effects ultimately prevail over the drug’s
analgesic action. An intriguing aspect of these
observations is the strict parallelism between
the behavior of non-neuronal cells in chronic
pain and that observed after repeated
administration of opioids.
THE CHALLENGE OF TREATING
THE ELDERLY WITH OPIOIDS
Chronic pain is highly prevalent in the elderly
] and calls for special attention . In
the period 1995–2010 the prescription of
opioids for chronic non-cancer pain in this
population increased some ninefold (compared to
historic levels), despite the limited number of
studies conducted on the elderly [
Unfortunately, studies evaluating the effectiveness of
analgesics often exclude elderly patients,
especially those most vulnerable to pain and its
impact on their lives. As such, the actual
efficacy and safety profile of analgesics, especially
opioids, in this population remains largely
unknown—especially for long-term treatment
]. Moreover, pharmacokinetic and metabolic
changes associated with aging render the
elderly vulnerable to the deleterious effects
including overdosing, associated with analgesic
use. Clinicians thus need to take into account
changes, even physiological, that develop with
age and the potential impact that they can have
on therapeutic actions of analgesics.
Age-dependent changes involving
nonneuronal cells negatively influence the
development of more serious side effects caused by
chronic opioid treatment [
]. As we age, mast
cells and microglia become more sensitive to
stimuli that affect their activation: both have
a lower activation threshold and respond with
more intense and lasting action over time
]. These changes in reactivity are referred
to as immunosenescence [
Immunosenescence is accompanied by an increased
sensitivity to pro-inflammatory mediators with a
consequent rise in mast cell degranulation. As
with microglia, morphine also activates mast
cells, resulting in the release of inflammatory
cytokines, neuropeptides such as SP and
tryptase, leading to activation of peripheral
nerve terminals and increased pain
55, 70, 71
]. Microglia in the elderly display
what may best be described as a primed
phenotype (Fig. 2), which is present also in
traumatic brain injury and neurodegenerative
]. The principal difference between
the two phenotypes lies in the resolution time
of activation. Resting microglia undergoes
brief activation intended to be beneficial and
aimed at recovering tissue homeostasis.
Primed microglia upon stimulation remains
activated for a prolonged period with an
abundant production/release of
pro-inflammatory cytokines that impede the resolution
and tissue homeostatic recovery. Experimental
models of neurodegenerative diseases show
these events to be promoters of non-resolving
neuroinflammation. In these same models of
neurodegenerative diseases another glial cell
population, namely astrocytes—that produce
cytokines, chemokines and trophic factors
analogous to microglia—take on a primed
behavior and respond in an exaggerated
manner to noxious stimuli [
Conceivably, these non-neuronal cells in the elderly
might respond to long-term morphine
treatment by developing a phenotype typical of
primed cells: exaggerated, prolonged over
time, and associated with non-resolving
neuroinflammation. The end result may be a
more rapid development of tolerance,
addiction and hyperalgesia.
TO MODULATE OPIOID ACTIONS:
A PHARMACOLOGICAL RATIONALE
One approach to overcome the problem of
prolonged opioid use may be the addition of
another agent that effectively either reduces the
development of tolerance or potentiates the
drug efficacy, thus allowing the use of lower
doses of opioids. Classically, and even recently,
multimodal analgesia has been suggested for
acute pain [
]. Opioids can be administered
with non-steroidal anti-inflammatory drugs
(NSAIDs), but also with other molecules
(Table 1). There is some precedent for this type
of approach. For example, agents able to
modulate non-neuronal cell activity limit the
development of certain side effects attributed to
opium derivatives. Cromolyn, an inhibitor of
mast cell degranulation, but not the opioid
antagonist naltrexone, prevents granuloma
time. Primed microglia induce persistent
neuroinflammatory response, capable of damaging tissue integrity and
neuron function. Reproduced with permission from Fusco
et al. 
formation induced by intrathecal morphine
], and also reduces toxicity caused
by intravenous administration of the potent
synthetic opioid fentanyl [
propentofylline and pentoxifylline reduce glial
cell activation and block the development of
morphine tolerance in na¨ıve mice, as well as in
a model of neuropathic pain [
Pentoxifylline also has been found to reduce
morphine consumption in patients with
postoperative pain . The above is highly
questionable, however, given that its side effects
limit their prolonged use in persistent pain
Chronic inflammatory processes trigger a
program of resolution that includes the
production of lipid mediators with the capacity to
switch off inflammation [
]. Among these are
the N-acylethanolamines, which include
palmitoylethanolamide (PEA) [
]. These fatty
acid amides are formed from N-acylated
phosphatidylethanolamine by several pathways, but
Lipid mediators, like N-acylethanolamines, including PEA
Anandamide and PEA PEA
Phytocannabinoid D9-Tetrahydrocannabinol (D9
THC) and the synthetic CB1 receptor agonist CB55940
Block of N-methyl-D-aspartate (NMDA) glutamate
receptors in the presence of D9-THC
Different sites of analgesic action,
Reduce glial activation and block the [51, 77–81] development of morphine tolerance
Switch off inflammation [18, 83–100, 109–112]
Transient potential vanilloid type 1
(TRPV1) receptor action
Modulation of endocannabinoid system (ECS)
Attenuate development of oral morphine tolerance [96, 113–117] [104, 118, 119]
Reduction of glutamate transmission
mainly involving a membrane-associated
phosphatidylethanolamine-phospholipase D that generates the respective
N-acylethanolamine and phosphatidic acid [
enzyme then converts
N-palmitoyl-phosphatidyl-ethanolamine into PEA.
A number of observations support a PEA role
in maintaining cellular homeostasis by acting as
a mediator of resolution of inflammatory
processes (through an Autacoid Local Injury
Antagonism mechanism1[ALIA]); it is
synthesized/metabolized by microglia and mast cells;
it down-modulates mast cell [
microglia activation; [
] tissue levels of PEA
are increased on demand in brain areas involved
in nociception and in the spinal cord following
neuropathic pain induction, in human
conditions associated with pain [
], as well as in
settings associated with injury to nervous tissue
A growing body of preclinical studies
demonstrates the ability of PEA to reduce
inflammation and pain induced by various
acute stimuli. The effect of PEA administration
by different routes is dose-dependent [
The anti-inflammatory and analgesic effects of
PEA have been confirmed in models of chronic
] and chronic or neuropathic
86, 89, 99, 100
]. In these models,
prolonged treatment with PEA not only reduced
pain but also preserved peripheral nerve
morphology, reduced endoneural edema, the
recruitment and activation of mast cells, and
the production of pro-inflammatory mediators
at the injury site [
86, 89, 100
]. Taken together,
these data indicate that PEA, via regulation of
persistent inflammatory processes and the ALIA
mechanism, can directly intervene in nervous
tissue alterations responsible for pain, i.e., to act
as a disease-modifying agent . At the clinical
level PEA, in micronized and ultramicronized
forms (m-PEA; um-PEA), reduces pain and
disability associated with several chronic diseases
These results suggest that the PEA could be a
promising candidate for minimizing the risks of
chronic treatment with opioids mediated by
activation of non-neuronal cells. The most
compelling experimental evidence to date
supporting the premise that concomitant use of
PEA and opioids could be beneficial is the
demonstration of delayed development of
tolerance to the anti-nociceptive effects of
morphine in the setting of repeated administration
of both compounds [
administration of m-PEA doubled the number
of days (from 5 to 10) of morphine treatment
efficacy in two rat pain models (mechanical and
thermal pain threshold) [
]. As the authors
point out: ‘‘In spite of the potency and efficacy
of morphine, its clinical application for chronic
persistent pain is limited by the development of
tolerance to the anti-nociceptive effect.’’
Further, these authors used immunohistochemical
techniques to show that development of
tolerance to morphine was accompanied by an
increase in glial cell number in the spinal cord.
Glial cells release large amounts of
pro-inflammatory cytokines that sensitize pain
transmission neurons, and thus gradually counteract
morphine’s anti-nociceptive effects. PEA
markedly prevented the increase in glial cells and
thus prolonged the efficacy of morphine. The
authors concluded their study, stating that
‘‘Multiple properties of PEA converge to an
interaction with signals evoked by morphine.
The evidence of a delayed development of
tolerance to the anti-nociceptive effects of
morphine in the presence of PEA suggests a possible
application of this endogenous compound in
opioid-based therapies’’ [
]. Clinically, m-PEA
administered with generally ineffective doses of
oxycodone produced good pain control with
excellent tolerability, suggesting the possibility
of combining the two molecules in order to
reduce opioid dose and consequent undesirable
What is the molecular basis underlying the
effects of PEA? PEA acts on many cell types,
including immune-derived non-neuronal
cells—in particular, microglia and mast cells—
which are involved in pain signaling but not
directly in the transmission of pain perception
]. A number of studies point to PEA being a
ligand for peroxisome proliferator activated
receptor (PPAR)a, one of a group of nuclear
receptor proteins that function as transcription
factors regulating the expression of genes. The
primary function of PPAR-a is as a fatty acid
sensor that regulates lipid and lipoprotein
metabolism and energy homeostasis through
the activation of several target genes.
PPAR-aand c-isoforms in particular are associated with
pro-inflammatory events. PEA
99, 105, 106
] and neuroprotection
] were either absent in PPAR-a null
mice or blocked by PPAR-a antagonists. An
‘entourage effect’ has also been hypothesized to
explain the pharmacological actions of PEA,
whereby PEA enhances the anti-inflammatory
and anti-nociceptive activity of other
endogenous compounds by potentiating their affinity
for a receptor or by inhibiting their metabolic
]. Anandamide (AEA) is a
candidate molecule, as it possesses
anti-inflammatory and anti-nociceptive effects. AEA and its
congeners like PEA have in common the
transient potential vanilloid type 1 (TRPV1)
receptor action. The TRPV1 receptor, a non-selective
cation channel expressed in small diameter
sensory neurons, is activated by noxious heat,
low pH and capsaicin. AEA itself is a TRPV1
receptor agonist, and PEA enhances AEA
stimulation of the human TRPV1 receptor [
] in a
cannabinoid CB2 receptor antagonist-sensitive
fashion (although PEA shows no appreciable
affinity for either CB1 or CB2 receptors)—which
could be interpreted as PEA acting indirectly by
potentiating AEA actions [
mast cells [
], and cortical[
] and spinal
] microglia all reportedly express
TRPV1 receptors. As the above
receptors/pathways may also be influenced by opioids’ actions,
it is not unreasonable to propose that PEA,
acting through the same receptors (CB1, PPAR,
TRPV1) has the potential to be a relevant
modulator of opioid activity. PEA may also
enhance the levels of the endocannabinoid
2-arachidonoylglycerol and potentiate its
actions at TRPV1 channels, observations which
effectively widens the ‘entourage’ effect of PEA
The potential for PEA to interact with the
opioid system may lie in its ability to modulate
the endocannabinoid system (ECS)—which in
turn influences the response to opioids through
the opioid system. Elements of the ECS
comprise the cannabinoid receptors CB1 and CB2, a
family of nascent lipid ligands, the
‘endocannabinoids’ (exemplified by AEA and
2-arachidonoylglycerol) and the machinery for
their biosynthesis and metabolism. PEA appears
to be a ligand for peroxisome proliferator
activated receptor (PPAR)a [
], one of a group of
nuclear receptor proteins that function as
transcription factors regulating the expression of
genes. PPAR-a- and c-isoforms in particular are
associated with pro-inflammatory events.
Interest in PPARs as potential targets for treating
drug addiction arose from study of the ECS,
which is thought to be involved in the addictive
properties of drugs [
]. Recently, Paterniti
et al. [
] demonstrated that PPAR-c and
PPARd are also targets for PEA in protecting the spinal
cord against pro-inflammatory insults, not by a
direct action but probably mediated by
cannabinoid CB1 receptor-dependent changes
in PPAR expression. As the above
receptors/pathways may also be influenced by opioid
actions, it is not unreasonable to propose that
PEA, acting through the same receptors, has the
potential to be a relevant modulator of opioid
activity. Concerning PPAR-c modulation of
opioids effects, recent studies [
] showed that
oral administration of the PPAR-c agonist
pioglitazone attenuated morphine-induced
tolerance, an effect attributed, at least in part, to its
anti-inflammatory properties against morphine.
Pioglitazone action was reversed by a selective
PPAR-c antagonist. These findings support the
notion that PPAR-c interaction may be relevant
with regard to both tolerance and dependence.
A role for PPAR-c cannot be discounted in view
of a report describing that PEA may act also as
an agonist of PPAR-c in protecting the spinal
cord against pro-inflammatory insults [
Both the phytocannabinoid
D9-tetrahydrocannabinol (D9-THC) [
] and the synthetic
CB1 receptor agonist CB-55940 [
determined to attenuate the development of
oral morphine tolerance. Further, blocking
Nmethyl-D-aspartate (NMDA) glutamate receptors
in the presence of D9-THC was more effective
than D9-THC alone in reducing the
development of tolerance, which may have been due to
pre-synaptic CB1 receptor agonists acting to
reduce glutamate transmission, a reduction
amplified when NMDA receptors are blocked
]. The CB1 and NMDA receptor systems
may thus play a key role in the behavioral
plasticity associated with chronic morphine
The notion that the endocannabinoid and
opioid systems are closely linked is supported
also by data demonstrating that the L-arginine/
nitric oxide (NO)/cyclic guanosine
monophosphate (cGMP) pathway participates in
peripheral anti-nociception produced by l-, j- or
dopioid receptor agonists, non-steroidal
analgesics, and a-(2C)-adrenoceptor agonists [
a rat paw model of hyperalgesia induced by
intra-plantar injection of prostaglandin E2, the
local peripheral anti-nociceptive effect PEA was
antagonized by a selective neuronal NO
synthase inhibitor and by a non-selective NOS
inhibitor. Exogenously administered PEA was
able to induce NO release, while the
cGMPphosphodiesterase inhibitor zaprinast
potentiated the anti-nociceptive effect of low-dose PEA.
Thus, PEA appears able to activate neuronal NO
synthase, thus initiating the NO/cGMP pathway
and inducing peripheral anti-nociceptive
effects—a pathway common to that elicited by
l-, j- or d-opioid receptor agonists.
The three major opioid receptor families, l, d
and j are activated by endogenous opioid
peptides (enkephalins, endorphins, and
dynorphins), and the opioid drugs. In addition to
pain modulation and addiction, opioid
receptors are widely involved in various physiological
and pathophysiological processes, including the
regulation of membrane ion homeostasis, cell
proliferation, emotional response, epileptic
seizures, immune function, feeding, obesity,
respiratory and cardiovascular control as well as
some neurodegenerative disorders [
The ECS plays a major role in the control of
pain as well as in mood regulation, reward
processing and the development of addiction.
Both opioid and cannabinoid receptors are
coupled to G proteins expressed throughout the
brain’s reinforcement circuitry. Given the
central role that PEA may play in the ECS, it is not
surprising that it can influence the effects of
opioids. The existing literature clearly
demonstrates that PEA either directly or
indirectly affects a variety of receptors and pathways
known to modify the responses to opioids such
Because opioid-induced neuroinflammation
is implicated in the development of tolerance to
these analgesic substances, intervention in
pathways that lead to neuroinflammation and
its resolution is an attractive strategy for pain
therapeutics. PEA has been extensively studied
in this setting of neuroinflammation [
Current evidence supports the concept that by
acting on mast cells and glia, PEA promotes the
body’s capacity for self-defense against
(neuro)inflammation (ALIA mechanism).
Indeed, initial investigations provide evidence
favoring the use of PEA in conjunction with
]. Pharmacological studies
demonstrating the ability of PEA to affect opioid and
cannabinoid receptors/pathways, coupled with
opioid effects being modulated by the ECS,
allow us to infer that opioid analgesic effects
may be potentiated or last longer with reduced
tolerance development. Building on two basic
observations, namely, that opioids reduce
chronic/neuropathic pain perception and PEA
modifies the underlying cause(s) of this pain, we
are drawn to the conclusion that usage of PEA
and opioids, either in fixed combinations or by
concomitant administration, merit larger
clinical trials to confirm these observations in
humans. Considering the benefit/risk of the
PEA, these results suggest that PEA, possibly
associated with antioxidant molecules, can be
an innovative therapeutic tool to enhance the
effects of opioid analgesics and impede the
development of opioid tolerance and
Funding. The paper has been supported in
part by MIUR, ‘‘PON Ricerca e Competitivita`
2007–2013, Project PON 1_02512’’. No funding
was received for the article processing charges.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Disclosures. Mariella Fusco is an employee
of the Epitech Group srl. Giustino Varrassi,
Stephen D. Skaper, Daniele Battelli, Panagiotis
Zis, Stefano Coaccioli, Maria Caterina Pace and
Antonella Paladini have nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously published data and
does not contain studies with human
participants or animals performed by any of the
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction
in any medium, provided you give appropriate
credit to the original author(s) and the source,
provide a link to the Creative Commons license,
and indicate if changes were made.
palmitoylethanolamide, an endogenous
peroxisome proliferator-activated receptor-alpha agonist,
modulates carrageenan-induced paw edema in
mice. J Pharmacol Exp Ther. 2007;322:1137–43.
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