Analgesic Mechanisms of Antidepressants for Neuropathic Pain

Abstract

Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear. The inhibitory effects of these antidepressants for neuropathic pain manifest more quickly than their antidepressive effects, suggesting different modes of action. Recent studies of animal models of neuropathic pain revealed that noradrenaline is extremely important for the inhibition of neuropathic pain. First, increasing noradrenaline in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through α2-adrenergic receptors. Second, increasing noradrenaline acts on the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain. The mechanisms of neuropathic pain inhibition by antidepressants based mainly on experimental findings from animal models of neuropathic pain are discussed in this review.

Full text

Int. J. Mol. Sci. 2017, 18, 2483; doi:10.3390/ijms18112483 www.mdpi.com/journal/ijms
Review
Analgesic Mechanisms of Antidepressants for
Neuropathic Pain
Hideaki Obata
Center for Pain Management and Department of Anesthesiology, Fukushima Medical University,
1 Hikarigaoka, Fukushima-City, Fukushima 960-1295, Japan; obata@fmu.ac.jp; Tel.: +81-24-547-1533
Received: 22 October 2017; Accepted: 19 November 2017; Published: 21 November 2017
Abstract: Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat
chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of
neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear.
The inhibitory effects of these antidepressants for neuropathic pain manifest more quickly than their
antidepressive effects, suggesting different modes of action. Recent studies of animal models of
neuropathic pain revealed that noradrenaline is extremely important for the inhibition of
neuropathic pain. First, increasing noradrenaline in the spinal cord by reuptake inhibition directly
inhibits neuropathic pain through α
2
-adrenergic receptors. Second, increasing noradrenaline acts on
the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory
system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic
pain. The mechanisms of neuropathic pain inhibition by antidepressants based mainly on
experimental findings from animal models of neuropathic pain are discussed in this review.
Keyword: noradrenaline; 5-HT; dopamine; spinal cord; α
2
-adrenergic receptors; locus coeruleus;
spinal nerve ligation; hyperalgesia; allodynia; rats
1. Introduction
Although antidepressants were not originally designed to act as analgesics, they are reported to
have analgesic effects for chronic pain. Antidepressants have virtually no antinociceptive effects, but
are considered first-line drugs of choice for neuropathic pain [1–4] and treatment of fibromyalgia [5].
Specific antidepressants with analgesic effects include tricyclic antidepressants (TCA), which have
long been used, and serotonin noradrenaline reuptake inhibitors (SNRI), which are comparatively
new antidepressants. Selective serotonin reuptake inhibitors (SSRI), which are frequently used to
treat depression, are not effective against chronic pain [1–3].
2. Effects of Antidepressants on Neuropathic Pain Differ from Their Effects on Depression
Antidepressants, along with pregabalin/gabapentin (voltage-dependent calcium channels α2δ
subunit ligands) are used as first-line drugs for treating neuropathic pain [1–4]. Psychologic problems
play an important role in chronic pain. Protracted pain causes anxiety accompanied by a progressive
depressive state and enhanced pain sensations. Therefore, antidepressant medications may be
effective against chronic pain by their effects to improve the depressive state. Antidepressants inhibit
neuropathic pain, however, even when the patient is not in a depressive state [6]. In addition, the
effects of antidepressants on depression characteristically take approximately two to four weeks to
be observed from the time the drug is first taken, whereas the analgesic effects on chronic pain
manifest in as little as few days to one week [7]. Therefore, the analgesic effects of antidepressants on
chronic pain likely involve a mechanism different from that mediating their antidepressive effects.

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3. Noradrenaline Is Extremely Important for Inhibiting Neuropathic Pain
The pharmacologic effects of antidepressants involve binding to noradrenaline and serotonin (5-
HT) transporters. Reuptake of these neurotransmitters is inhibited, leading to increased levels of
noradrenaline and 5-HT in the synaptic cleft [8–11]. What type of antidepressants is most effective
against neuropathic pain? The “number needed to treat” (NNT) is an index used to compare the
efficacy of medications based on the results obtained in a variety of clinical studies (meta analysis)
and is represented as the number of patients treated for whom pain was reduced by up to 50%, with
a smaller numerical value indicating a stronger efficacy [12,13]. According to a report from Finnerup
et al., the NNT of TCA to inhibit peripheral neuropathic pain is approximately 2–3. The NNT of dual-
type TCAs (e.g., amitriptyline, imipramine, clomipramine), which inhibit reuptake of both
noradrenaline and 5-HT, is 2.1. The NNT for noradrenaline reuptake inhibitors (nortriptyline,
desipramine) is approximately 2.5 [14]. The NNT for SNRI is 5.0 and for SSRI is 6.8 in painful
polyneuropathy [2]. Based on these results, an antidepressant that inhibits reuptake of both
noradrenaline and 5-HT has stronger analgesic effects than a drug that selectively inhibits reuptake
of only one of these neurotransmitters, and noradrenaline plays a greater role than 5-HT in the
analgesic action.
4. Noradrenaline Inhibits Neuropathic Pain in the Spinal Cord
Noradrenaline reuptake inhibition enhances analgesic effects, mainly through α2-adrenergic
receptors in the dorsal horn of the spinal cord. The α2-adrenergic receptors are coupled to the
inhibitory G protein (Gi/o), which inhibits the presynaptic voltage-gated Ca2+ channels in the dorsal
horn of the spinal cord that inhibits the release of excitatory neurotransmitters from primary afferent
fibers. At the same time, G protein-coupled inwardly rectifying K+ channels are opened on the post-
synaptic spinal cord dorsal horn cells, the cell membranes are hyperpolarized, and excitability is
decreased [15]. While activation of the α2-adrenergic receptors of the spinal cord dorsal horn has
weak antinociceptive effects against noxious stimuli, extensive research indicates that it is extremely
effective against allodynia and hyperalgesia associated with neuropathic pain [16,17]. The reason for
the increasing efficacy for hypersensitivity of spinal α2-adrenergic receptors stimulation is that nerve
injury changes the function of α2-adrenergic receptors in the dorsal horn of the spinal cord [18,19],
while at the same time the interaction with the cholinergic interneurons strengthens [20–23]. Our
findings support the importance of α2-adrenergic receptors in the spinal cord dorsal horn for the
inhibition of neuropathic pain. We used a rat model of neuropathic pain known as spinal nerve
ligation (SNL). In this procedure, the L5 spinal nerve is ligated on one side [24]. When mechanical
pressure is applied to the ipsilateral hind paw on the ligated side using a paw-pressure test, the
withdrawal threshold decreases and mechanical hyperalgesia develops. Intrathecal administration
of an α2-adrenergic receptor agonist, dexmedetomidine, leads to the release of acetylcholine to the
spinal cord and mechanical hyperalgesia is inhibited through the muscarinic receptors [16]. In
animals with nerve injury, the α2-adrenergic receptors expressed in the cholinergic interneurons of
the spinal cord dorsal horn are coupled with excitatory G protein (GS) by the action of brain-derived
neurotrophic factor (BDNF) through TrkB receptor and acetylcholine is released by stimulation of the
α2 adrenergic receptors [23]. As a result, muscarinic receptors, which induce gamma-aminobutyric
acid (GABA) release [25,26], contribute to the inhibitory effects of α2-adrenergic receptor activation
for neuropathic pain (Figure 1). Thus, the pain relief mediated by noradrenaline in the dorsal horn of
the spinal cord is more effective for neuropathic pain than for nociceptive pain due to plastic changes
of the α2-adrenergic receptors.

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Figure 1. Schematic illustration of analgesic effects of antidepressants and noradrenaline in the dorsal
horn of the spinal cord. Antidepressants increase noradrenaline via blocking of noradrenaline
transporters at the terminal of the descending noradrenergic fiber from the locus coeruleus.
Noradrenaline inhibits acute pain through α2-adrenergic receptors by pre-synaptic (inhibit
neurotransmitters release) and post-synaptic (hyperpolarize cell membranes) mechanisms. In
neuropathic pain states, however, α2-adrenergic receptors in the cholinergic interneurons change
from inhibitory to excitatory through G-protein switch (from Gi to Gs) by the effect of brain-derived
neurotrophic factor (BDNF) increasing after nerve injury. Released acetylcholine bind to muscarinic
receptors, by which produce analgesia thorough GABA release. PAF; primary afferent fibers, NA;
noradrenaline, DHN; dorsal horn neurons, ACh; acetylcholine, Red circle; noradrenaline, Blue circle;
acetylcholine, Green circle; GABA, Pink circle; excitatory neurotransmitters.
Intraperitoneal administration of duloxetine, an SNRI, to SNL rats increases the withdrawal
threshold for at least 4 h, but the effect disappears after 24 h. When duloxetine is administered for
three consecutive days, the withdrawal threshold gradually increases and returns to pre-SNL levels.
This increase in the withdrawal threshold is reversed by intrathecal injection of idazoxan, an α2
adrenergic receptor antagonist, and the amount of noradrenaline in the dorsal horn of the spinal cord
increases after three daily injections of duloxetine [27] (Figure 2). In addition, in animals pretreated
with a noradrenergic neurotoxin (DSP-4), the antihyperalgesic effect of duloxetine is weakened [28].
Intraperitoneal administration of amitriptyline, a TCA, over consecutive days gradually increases the
withdrawal threshold, but this antihyperalgesic effect is reversed by intrathecal injection of an α2-
adrenergic antagonist [28].
Noradrenaline in the dorsal horn of the spinal cord is increased by a single intraperitoneal
injection of antidepressants such as amitriptyline (TCA), duloxetine and milnacipran (SNRI), or
fluoxetine and paroxetine (SSRI) (Figure 3). In addition, a single administration of paroxetine
produces an anti-hyperalgesic effect, which is inhibited by intrathecal injection of an α2-adrenergic
receptor antagonist [29] Fluoxetine and paroxetine have weak inhibitory effects on noradrenaline
transporters [30,31], and thus their effects to increase noradrenaline are likely indirect. These findings
suggest that the increase in noradrenaline in the spinal cord plays a crucial role in the inhibitory
effects of antidepressants on neuropathic pain.

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Figure 2. Antihyperalgesic effects of duloxetine in rats after nerve injury by noradrenaline increase in
the spinal cord. (A) Effects of three daily injections of duloxetine on hind paw mechanical
hyperalgesia after spinal nerve ligation (SNL) in rats. Rats were administered duloxetine
(10 mg/kg/day, subcutaneous injection) or vehicle for three consecutive days. Each day, withdrawal
thresholds in ipsilateral hind paw were measured at time 0 (baseline: before each duloxetine
injection), and 120 and 240 min after the injection. Three daily treatment increased baseline
withdrawal thresholds (time 0) of on days 3 and 4 than on day 1 (* p <0.05 compared with the
duloxetine group at time 0 on day 1). Acute antihyperalgesic effects until 240 min after injection were
also observed. Then, rats were injected intrathecally (i.t.) with idazoxan, an α2-adrenoceptor
antagonist (30 μg/20 μL) or vehicle. The injection of idazoxan reversed the antihyperalgesic effect of
duloxetine (* p <0.05 compared with the vehicle group at each time-point). (B) Spinal cord tissue from
SNL rats injected with duloxetine (10 mg/kg/day) or vehicle for three consecutive days was
homogenized, and the noradrenaline content was measured. Noradrenaline was increased with
duloxetine treatment at both ipsilateral and contralateral to the SNL compared to the vehicle group
(* p <0.05). Data in this figure published from Ref. [27].
Figure 3. Percentage changes of noradrenaline, dopamine, and 5-HT levels in the dorsal horn of the
lumbar spinal cord in rats after intraperitoneal injection of 10 mg/kg of amitriptyline (TCA),
duloxetine (SNRI), milnacipran (SNRI), fluoxetine (SSRI) and Paroxetine (SSRI). Under isoflurane
anesthesia, microdialysis studies ware performed after thoracolumbar laminectomy,
and monoamines were measured by using high-performance liquid chromatography
with electrochemical detection. All monoamines were increased after injection of all antidepressants
(all p <0.05 compared to control; saline or vehicle, by two-way repeated-measures analysis of variance.
Some data in this figure published from Ref. [32]).

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5. Actions of Antidepressants on the Locus Coeruleus
The locus coeruleus (LC) comprises a group of nerve cells containing noradrenaline located
bilaterally in the brain. The LC has the greatest amount of noradrenaline in the central nervous system
and is located on the right and left of the posterior brainstem facing the fourth ventricle [33,34].
Noradrenergic nerve fibers project virtually throughout the entire central nervous system and play a
role in sleep, wakefulness, cognition, learning and stress in the brain [35–37]. In the spinal cord,
noradrenergic nerve fibers regulate endogenous analgesia, posture and motion, the autonomous
nervous system, and other vital functions [38–40]. The neuronal activity of the LC is characterized by
a tonic (autonomous activity) mode and a phasic (activity that reacts to stimulus) mode. Phasic
activity is an excitatory reaction within a short period of time in which stimuli induce the release of
an excitatory amino acid (mainly glutamic acid) in the LC. Phasic activity during the tonic activity
mode at a medium level from a lower level plays an important role in attention, movement and
concentration on outside stimuli, such as cognitive functions, endogenous analgesia and a variety of
other vital functions [35,41]. Descending noradrenergic neurons are an extremely important
mechanism of endogenous analgesia. In rats, the bilateral LC is excited phasically by noxious
stimulation, and releases noradrenaline through projections to the bilateral spinal cord dorsal
horn [38,41,42].
How does the activity of the descending noradrenergic inhibitory system from the LC change in
a neuropathic pain state? Noxious stimulation induced analgesia (NSIA) is an animal model in which
the intensity of endogenous analgesia can be measured. The withdrawal threshold in response to the
mechanical stimulus on the hind paw greatly increases after forepaw capsaicin injection by activation
of the endogenous analgesia [43]. An increase in noradrenaline in the spinal cord affects the
NSIA [41,43,44]. This means that the LC is activated phasically due to the pain induced by the
capsaicin, and the noradrenaline that is released to the spinal cord mediates antinociceptive effects
through α2-adrenergic receptors. When the same experiment was carried out using animal models of
neuropathic pain (SNL animals), the NSIA was no longer recognized six weeks after nerve injury (an
increase in the withdrawal threshold of the hind paw no longer occurred when capsaicin was
administered to the forepaw), and the noradrenaline is not increased in the spinal cord [27,41,44]. At
this time, the tonic nerve activity of the LC increased due to nerve injury, but the phasic reactivity to
the noxious stimuli disappeared [41]. Based on these results, the phasic activity of the neuronal cells
of the LC gradually declined in the neuropathic pain model after a long period of time had passed
from the nerve injury, and the descending noradrenergic inhibitory system was impaired.
In animals with nerve injury and impaired NSIA, administering duloxetine and amitriptyline
over several consecutive days recovers the NSIA [27,44]. Although the increase in noradrenaline in
the spinal cord induced by these antidepressants plays a part in the NSIA recovery, it is possible that
the effect of the drugs on the LC contributed to the effect. The LC receives inputs from a variety of
sites of the central nervous system and its activity is controlled by both noradrenaline and 5-HT [45].
Antidepressants increase noradrenaline around the LC [46], and inhibit the activity of the LC through
α2- adrenergic receptors [47,48]. In contrast, another report suggests that when duloxetine and
desipramine are administered consecutively, the increased noradrenaline desensitizes the
α2-adrenergic receptors in the LC [49]. In animal models of neuropathic pain, the reaction of the LC
to noxious stimuli differs from that in normal animals due to sensitization via N-methyl-D-aspartic
acid (NMDA) receptors, but this report indicates that the reaction is normalized by the consecutive
administration of duloxetine and desipramine [49].
Furthermore, a previous study demonstrated that nerve injury increases the basal extracellular
glutamate concentration in the LC [41], which may reduce noxious stimulation-evoked glutamate
release, thereby diminishing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)
receptor-mediated LC activation, which is important for inducing NSIA. Another previous study
demonstrated that antidepressants increased BDNF levels in astrocyte cultures [50]. BDNF triggers
AMPA receptor GluA1 phosphorylation and regulates trafficking of the AMPA receptor to the cell
membrane [51]. Therefore, antidepressants may reactivate impaired LC function after nerve injury
by increasing BDNF levels.

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6. The Role of 5-HT
Many antidepressants block 5-HT transporters, leading to increased 5-HT in the synaptic cleft.
The role of 5-HT on the inhibitory effects of antidepressants against neuropathic pain, however, is
unclear. Although SSRIs are popular drugs for the treatment of depression, they are not
recommended for the treatment of neuropathic pain [1–3]. Despite some reports of their effectiveness
in randomized controlled trials in patients with chronic pain, the NNT for SSRIs is higher than that
for TCA and SNRI [2,14]. For this reason, 5-HT is thought to play a less important role than
noradrenaline in the inhibition of neuropathic pain, but simultaneous administration of
noradrenaline and 5-HT selective reuptake inhibitors in an animal experiment produce a synergistic
analgesic effect [52], suggesting that 5-HT has auxiliary actions.
5-HT in the dorsal horn of the spinal cord greatly contributes to pain modulation. Inhibitory
5-HT1A receptors, and excitatory 5-HT2A/2C, 5-HT3, and 5-HT7 receptors that strongly contribute to
nociceptive transmission are expressed in the dorsal horn of the spinal cord [53–56]. These receptors
are present in the pre-synaptic terminals of primary afferent nerve fibers, inhibitory interneurons,
excitatory interneurons and projection neurons, and modify nociceptive transmission. When the pain
sensation reaches the brain, the descending inhibitory system is mobilized from a variety of sites in
the cerebral cortex and activates the periaqueductal gray (PAG) [56,57]. The PAG closely controls the
rostroventromedial medulla (RVM) and modifies pain via projecting fibers from the RVM to the
dorsal horn of the spinal cord [56–58]. The RVM includes the nucleus raphe magnus, which projects
abundant serotonergic fibers to the spinal cord dorsal horn [58]. Descending serotonergic projections
from the RVM to the spinal cord dorsal horn exert both inhibitory and facilitatory effects on pain
processing depending on the pain state, acute or chronic [58–60]. In neuropathic pain models, many
studies reported that ablation of descending 5-HT pathways inhibit pain hypersensitivity [61–63],
and have also demonstrated that nerve injury induces descending facilitation by activating spinal 5-
HT3 receptors [64,65]. Activation of descending serotonergic neurons form the RVM is required,
however, for this descending facilitation to occur. In contrast, direct intrathecal injection of 5-HT or a
5-HT3 agonist inhibits allodynia in a rat neuropathic pain model [66,67]. Systemic administration of
paroxetine, an SSRI, produces an anti-hyperalgesic effect in a rat model of neuropathic pain through
spinal 5-HT3 receptors [29], because the drug directly increases 5-HT in the spinal cord by inhibiting
5-HT transporters.
Several lines of evidence suggest that 5-HT receptor function changes in neuropathic pain states.
Although 5-HT2A receptors in the spinal cord dorsal horn contribute to the suppression of
neuropathic pain [68–70], the inhibitory effects of systemically administered SSRIs on hyperalgesia
after nerve injury are stronger when spinal 5-HT2A receptors are disrupted from their associated PDZ
proteins by intrathecal injection of a peptide (TAT-2ASCV) [71]. Systemic administration of a 5-HT1A
receptor agonist (NLX-112) strongly inhibits inflammatory pain, but is less effective against
neuropathic pain [72].
Thus, there are many reports suggesting a less important role for 5-HT in inhibition of
neuropathic pain compared to acute pain. Increased 5-HT in the spinal cord by antidepressants may,
however, play some inhibitory role for neuropathic pain.
7. The Role of Dopamine
Descending dopaminergic neurons, which project from the mesolimbic A11 dopamine cell
group to the spinal cord dorsal horn, release dopamine in the dorsal horn of the spinal cord and
inhibit nociceptive transmission by mediating dopamine D2-like receptors [73,74]. Buproprion, a
dopamine noradrenaline reuptake inhibitor, increases noradrenaline and dopamine levels in the
spinal cord and suppresses hyperalgesia in a rat neuropathic pain model through α2-adrenergic
receptors and D2-like receptors [75]. No other antidepressants are reported to strongly inhibit
dopamine transporters. Nevertheless, we demonstrated that intraperitoneal administration of
amitriptyline (TCA), duloxetine and milnacipran (SNRI) and fluoxetine (SSRI) at a dose of 10 mg/kg,
all increased dopamine in the spinal cord and inhibited hyperalgesia in a rat model of neuropathic
pain through D2-like receptors [32]. There are few dopamine transporters in the frontal cortex and

Int. J. Mol. Sci. 2017, 18, 2483 7 of 12
reuptake of dopamine is mediated by noradrenaline transporters [76]. It is unclear why
antidepressants increase dopamine levels in the spinal cord.
Dopaminergic neurons in the ventral tegmental area (A10) release dopamine in the nucleus
accumbens and enhance analgesic activity through D2-like receptors [77–79]. A previous study
demonstrated that duloxetine (25 mg/kg orally) increases dopamine in the nucleus accumbens, but
amitriptyline and maprotiline (both 50 mg/kg orally) do not have this effect [80]. Dopamine enhances
the antinociceptive effects in the striatum [81,82]. Although it is unclear whether antidepressants
increase dopamine in these brain areas, dopamine increases in the central nervous system are likely
to play a role in the inhibitory effect of antidepressants on neuropathic pain.
8. Other Actions
Antidepressants have a number of other actions in addition to increasing monoamines that may
contribute to the inhibition of neuropathic pain. First, they act as sodium channel blockers [83,84].
Sodium channel blockers inhibit ectopic discharges occurring when there is nerve damage, thereby
inhibiting neuropathic pain [85,86]. Second, some antidepressants act as NMDA receptor
antagonists [87,88]. NMDA receptors, which are expressed in the neurons of the dorsal horn of the
spinal cord, induce wind-up and central sensitization result in contribute to the onset and
maintenance of neuropathic pain [89,90].
TCAs also act as α1-adrenergic receptors [91], calcium channel blockers [92], potassium channel
activators [93], modulate the adenosine system [94] and increase GABA-B receptor function [95].
They activate opioid receptors [96], inhibit the production of nitric oxide, prostaglandin E2 [97] and
have a variety of other actions that may inhibit neuropathic pain in a complex manner.
9. Conclusions
The main mechanism of antidepressants that inhibit neuropathic pain is first, to increase
noradrenaline in the spinal cord, and second, to act on the LC, thereby directly inhibiting pain and
activating the impaired descending noradrenergic inhibitory system. Dopamine and 5-HT also
increase in the central nervous system and may enhance the inhibitory effects of noradrenaline in an
auxiliary manner.
Conflicts of Interest: The authors declare no conflict of interest.
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