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Title: Deep Brain Stimulation of the Lateral Habenula to Treat Opioid-Induced Hyperalgesia

Irene Quan, Qi K Zuo, Wanhong Zuo, Mohamed A Bouhara, Jiang-Hong Ye

Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New
Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey, USA.

Abstract: Opioid-induced hyperalgesia (OIH) is an adverse side effect of chronic opioid use characterized by a
heightened sensitization towards pain. While the mechanisms behind OIH are still yet to be understood, many
existing studies point to the neuroplasticity of the central glutaminergic system as a likely cause. Current treatment
regimens remain limited and often lead to exacerbated hyperalgesic effects or even risks of overdose. In order to
mitigate OIH and prevent the loss of opioid efficacy, we propose deep brain stimulation (DBS) as a potential
treatment option. DBS is a procedure that targets specific areas of the brain using electrodes and has proven
effective for treating various neurological movement disorders and, more recently, chronic pain. Recent
experimental data has shown that DBS can alleviate aversive events in the lateral habenula (LHb), an area of the
brain that is linked to reward-negative events such as depression, pain, and anxiety. In this review, we will first
introduce DBS in its clinical and preclinical uses and discuss its potential as a treatment for OIH. We will then
analyze the opioid epidemic, as well as how the neurocircuits of LHb may contribute to the symptoms of this global
crisis. Despite the gaps in knowledge that remain about the exact mechanisms, DBS to treat OIH is a novel idea that
may be very effective. This review will conclude by projecting future directions for research that can help further
improve our understanding of this subject.

Keywords: deep brain stimulation; lateral habenula; opioid-induced hyperalgesia; opioids; opioid signaling; opioid
tolerance; pain
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1. Introduction
Deep brain stimulation (DBS) is a surgical procedure that uses electrodes to electrically stimulate specific
brain regions [1]. By implanting a pacemaker-like device into the brain, constant electrical signals can be delivered
to change the activity of targeted brain cells [2]. DBS has primarily been used to treat movement disorders,
including Parkinson’s disease (PD), essential tremor, and dystonia [3]. The creation of the technique can be
attributed to Alim-Louis Benabid and his colleagues, who discovered DBS as an effective treatment for motor
symptoms associated with PD in the 1980s at the Joseph Fourier University in Grenoble [4]. In 1997, the US Food
and Drug Administration approved DBS for clinical use and was quickly followed by the approval of DBS for PD in
2002, dystonia in 2003, and severe OCD in 2009 [5]. In particular, chronic high-frequency stimulation (HFS) was
found to be clinically beneficial for the treatment of these movement disorders [6]. Since then, DBS has rapidly
advanced in medicine, as more than 100,000 patients have undergone the procedure [7]. Because of the immense
success of DBS, especially in its reversibility, adaptability, and low morbidity, its purposes have diversified to treat
many other illnesses, including depression and drug abuse disorders [5, 8]. More specifically, both animal and
human studies have shown that DBS may be effective in regulating addictive behaviors to alcohol, cocaine, heroin,
morphine, and nicotine [9].
This discussion of DBS will be centered around opioid-induced hyperalgesia (OIH) and the lateral
habenula (LHb) as a potential therapy target. In general, opioids are the standard analgesics for the treatment of
pain; however, prescription opioid misuse and abuse have escalated drastically over the past few decades, creating
one of the largest drug epidemics in the world. Today, over 2.1 million Americans suffer from opioid addiction, and
over 130 people in the US die every day from opioid overdoses [10-11]. Despite being a common analgesic, the use
of opioids produces an abnormal nociceptive effect known as OIH, which occurs when a patient who is exposed to
opioids becomes increasingly tolerant of larger doses of the drug, resulting in a notable increase in pain sensitivity
[10]. Many mechanisms are still not completely understood in this paradoxical phenomenon, and a wide range of
hypotheses are currently being offered as potential answers [12].
While knowledge regarding the mechanisms of OIH is steadily increasing, the clinical implications
continue to be limited. Consequently, this review will delve into the morphological and physiological properties of
the LHb, a region of the brain that is implicated in nociception and expresses an abundance of mu-opioid receptors,
which are important targets for drug abuse and pain [13]. Given the effectiveness of DBS in the LHb in attenuating
depression [14], we will be able to analyze the efficacy of extending its applications to the pain sensations
experienced in OIH.

2. Lateral Habenula

The LHb is one of two discrete habenular nuclei located in the most caudal part of the epithalamus, with
the other being the medial habenula [15]. Both of these structures are vital in the inhibition of the monoaminergic
centers of the brain [16], which causes subsequent depressive-like and addictive behaviors. The majority of LHb
neurons are glutamatergic, though there has been evidence suggesting several GABAergic interneurons in the
network as well [17]. Many afferents are received by the LHb through the stria medullaris, including the globus
pallidus (or non-primate equivalent entopeduncular nucleus), lateral hypothalamus, paraventricular nucleus, lateral
preoptic area, ventral pallidum, and basal forebrain, which consists of the lateral septum, nucleus accumbens (NAc),
and diagonal band nuclei [15]. In addition, cortical afferents come from the anterior cingulate and anterior insular
cortex, which both have pain-responsive neurons [18]. The LHb also inhibits monoaminergic transmission, most
notably dopamine (DA) and serotonin (5-HT), with efferent connections in the substantia nigra pars compacta
(SNc), ventral tegmental area (VTA), and median and dorsal raphe nuclei (DRN) [19]. Outputs from the LHb have
excitatory effects on GABAergic neurons in the rostromedial tegmental nucleus (RMTg) as well, and optogenetic
stimulation of the RMTg inputs has been used to produce aversion [20]. Furthermore, subpopulations of RMTg
inhibit DA neurons from the VTA, as well as serotonergic neurons from the DRN [ 21]. It has also been
hypothesized that the LHb projects onto GABA cells in the VTA to indirectly inhibit the release of DA, though there
has been limited evidence to support this claim [19].
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Figure 1. Sagittal rodent brain section of afferent and efferent connections of the lateral habenula (LHb; shown in
purple). Afferent connections are shown in blue, efferent connections are shown in red, and bidirectional
connections are shown in green. LHb, lateral habenula; PAG, periaqueductal gray; DRN, dorsal raphe nucleus;
MRN, median raphe nucleus; RMTg, rostromedial tegmental nucleus; VTA, ventral tegmental area; EPN,
entopeduncular nucleus; LH, lateral hypothalamus; LPO, lateral preoptic area; VP, ventral pallidum; NAc, nucleus
accumbens; LS, lateral septum; mPFC, medial prefrontal cortex.

Because of the LHb’s ability to modulate the monoaminergic systems, it is crucial in reward processing,
motivation, cognition, and social behavior [22]. In particular, DA neurons are vital in the reward centers of the brain,
as they carry signals that direct motor controls and predict the maximization of reward gain [ 19]. A study that led a
visual saccade task with non-human primates found that in reverse responses, LHb neurons were excited by no-
reward-predicting targets, while DA neurons were excited by reward-predicting targets. When weak electrical
stimulation was performed on the LHb, further inhibition of DA neurons was observed. The paper proceeded to
describe the inhibition of LHb neurons as crucial for influencing the excitation of DA neurons [23].
Among the other monoamines that are controlled by the LHb, there is strong evidence to suggest that
decreased levels of 5-HT often play a role in depressive-like behaviors as well [24]. Many animal models of
depression have shown positive correlations between LHb activity and depression [25]. The LHb directly regulates
5-HT activity through GABAergic interneurons in the DRN, where the largest number of 5-HT neurons exist, while
it indirectly activates the RMTg to inhibit the release of 5-HT [26]. Thus, by inhibiting LHb activity, many
symptoms that accompany major depression disorder (MDD) are mitigated, including anxiety and pain sensitivity
[25, 27]. 5-HT has also been closely studied in its connections to pain sensations, showing that the manipulation of
5-HT levels causes a lower pain threshold and tolerance [28]. Within the LHb, lesions have been shown to inhibit
the analgesic effects of electrical stimulation in the LH, making it a prime area of study for pain signaling pathways
and a potential target for DBS [29]. The activity of the LHb and its regulatory effects on the levels of 5-HT further
support the relationship between depression and pain; reports have shown that 34-66% of patients with depression
have a certain degree of pain symptoms [30]. The comorbidity between depression and pain greatly contributes to
the LHb’s impact on drug abuse and addiction, as we will examine in regards to OIH.
The LHb’s influence in these behaviors has allowed researchers to target this region for drug abuse, most
notably cocaine, alcohol, and opioids. More specifically, the interest in drug addiction can be ascribed to its
convergence of both reward processing and aversion, behavioral characteristics that the LHb focuses on [ 31]. In
previous studies, repeated cocaine application increased firing in glutamatergic LHb neurons, while inhibition of
glutamate was able to reduce firing [31-32]. Similarly, recent studies concerning alcohol withdrawal have data
supporting the hypothesis that withdrawal from chronic ethanol drinking increases α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid receptors and Ca 2+/calmodulin-dependent protein II (CaMKII) activity in the LHb;
inhibiting this activity suppressed depression symptoms and alcohol intake [33]. Though the specific mechanisms of
the LHb in drug abuse disorders are still being studied, it is evident that the LHb plays an important role in drug
addiction and withdrawal.
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3. Deep Brain Stimulation in the Lateral Habenula

As aforementioned, the uses of DBS are currently being researched to treat other neuropsychiatric
disorders, including Tourette’s syndrome, obsessive-compulsive disorder, and MDD. The main issue is in finding
potential targets that can be further investigated in research so that it may become a clinically effective procedure in
the future. Previous targets that have proven potent in treating addiction, MDD, and pain include the NAc,
subthalamic nucleus, dorsal striatum, medial prefrontal cortex, and hypothalamus [9]. In these experiments, the
general stimulation calls for a strict set of parameters (monopolar cathodic; 1-5 V stimulus amplitude; 60-200 ms
stimulus pulse duration; 120-180 Hz stimulus frequency), where moderate to high stimulus rates have generated
significant improvements in neuropsychiatric disorders [34]. Other observations have been published to test the
efficacy of DBS using functional imaging, neurochemistry, neural recording, and neural modeling experiments; the
combined analyses likely attribute the mechanisms of DBS to its ability to modulate pathological networks within
the brain [35]. Due to the general inhibitory effect of DBS and the role of the LHb in modulating midbrain nuclei
activity, many studies have postulated that using DBS to target the LHb has promising outcomes in treating MDD
and substance use disorders [36].
The prevalence of MDD has led to a focus on DBS of the LHb to alleviate symptoms of treatment-resistant
depression [37]. This has been accomplished in numerous animal models by functionally inhibiting the LHb, thereby
causing an upregulation of the serotonergic, noradrenergic, and dopaminergic systems [38]. The results were
corroborated by a study modeled in rats that showed improved behavioral and chemical changes to chronic 28-day
stimulation, providing further evidence that a long-term treatment plan is ideal [39]. Another study demonstrated
that by using high-frequency DBS on LHb afferents, both presynaptic drive and depressive-like behaviors were
suppressed in rats [1]. In one particular case, DBS in the LHb was used to treat a patient who did not respond to any
other treatments, resulting in a full remission of MDD symptoms that she had been experiencing for 46 years [ 40].
Taking these results into consideration, LHb research may hold enormous potential in treating major affective
disorders.
MDD is also associated with feelings of chronic pain and anxiety, which are encoded by LHb signaling and
demonstrate the comorbid characteristics of pain and depression. To determine the role of the LHb in pain, several
behavioral and histochemical experiments were performed after painful stimuli were introduced, including the
forced swim test and sucrose preference test. The expression of CaMKII and activity of cytochrome-c oxidase in the
LHb and DRN increased, while 5-HT levels in the DRN decreased [41]. The VTA and SNc are also involved in the
response mechanisms to painful stimuli through the innervation of the LHb. DBS involving these pathophysiological
mechanisms has not been studied as extensively as those of MDD, though there is data suggesting that single-pulse
stimulation inhibited approximately 90% of the pain-activated neurons in the LHb [42]. In general, there is sufficient
evidence of the midbrain’s dopaminergic influence on LHb firing, as well as positive and negative feedback
pathways. As for the DBS in the LHb to treat OIH, there are currently no studies, but this review will give insight on
the feasibility and efficacy of DBS within these networks.

4. Opioid Signaling

The discovery of opioids in the 1970s revolutionized analgesic medication, creating new solutions as well
as new problems. Since then, multiple advancements have been made to better understand the endogenous opioid
system [43]. For one, researchers discovered that these opiates operated similarly to the endogenous opioid-like
peptides [43-44]. These findings were solidified by the naloxone-reversible analgesic effects caused by the
stimulation of specific opioid receptors [45]. The interaction between opioids and their respective receptors results
in a wide range of rewarding, stressful, and analgesic effects [46]. These include the following three primary
receptors: mu-opioid receptors (MORs), kappa opioid receptors (KORs), and delta-opioid receptors (DORs) [47-49].
These receptors make up the rhodopsin receptor subfamily of the G protein-coupled receptors (GPCR). GPCRs
consist of seven transmembrane domains, an extracellular N terminus for glycosylation, a third intracellular loop,
and a fourth intracellular loop made by the putative palmitoylation sites [50]. Many of these functions are regulated
through the Gi/o protein, as it helps regulate the specific adenylate cyclase (AC) isoforms involved in converting
adenosine triphosphate into cyclic adenosine monophosphate (cAMP), a secondary protein messenger [51].
For drugs with analgesic effects, including opioids, their potency is the highest when they act on MORs
[52], which participate in a widespread network of circuits throughout the body [53]. MORs play a critical role in
nociception, especially when MOR agonists can inhibit terminals of primary afferent nociceptors, nociceptive
signals in spinal dorsal horn neurons [54], and transmission in the anterior cingulate cortex [55]. This process
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eventually causes analgesia by activating pain-inhibiting neurons in the periaqueductal gray and the rostral
ventromedial medulla (RVM) [56]. Likewise, MOR-induced analgesia has been associated with G i-protein
signaling, which can also be related to some of the pain-relieving effects of KORs [57]. In addition to nociception,
MOR activation also inhibits GABAergic neurons in the RMTg, causing rewarding effects after opioid
administration [58]. Even though MORs are the main target in mediating analgesic and rewarding effects, an
increasing amount of studies have been conducted to show that KOR agonists help produce negative, stress-like
responses, and DOR agonists help produce positive, anxiolytic effects [59].
Recently, evidence of the role of MORs in the LHb has surfaced, as seen when morphine, a MOR agonist,
was injected into the LHb and directly produced analgesia [53]. Given the LHb’s ability to encode aversive states
and its relationship with MORs, morphine may disrupt pain-related signaling in the LHb [60]. Also, morphine
withdrawal resulted in increased Fos expression in the LHb, suggesting that the lack of morphine increases neuronal
firing [61]. However, some controversial evidence has suggested that the LHb had both excitatory and inhibitory
responses to morphine, which may be an indication of a dual modulation of glutamatergic transmission [62].
Evidently, this nociceptive process is the intended effect of opioids, and OIH is an abnormal paradoxical response.

5. Opioid Tolerance

The term tolerance in relation to the analgesic effects of opioids refers to the reduction in desired effects
after opioid exposure [63]. For example, in one particular instance in human subjects, the analgesic effects of
remifentanil were reduced to a quarter of its peak value after three hours of constant infusion [63-64]. The
development of analgesic tolerance can significantly decrease the clinical effects of opioids, requiring further
increases in doses. Because of this, the specific cellular and molecular mechanisms have been a topic of focus for
the past few decades [64]. There are numerous characteristics of opioid tolerance that are like those of OIH;
therefore, it is important to first consider the possible mechanisms behind opioid tolerance before discussing OIH.
Answers regarding the exact mechanisms behind opioid tolerance have largely been elusive, but recent
studies have led to implications ranging from MOR desensitization to protein development caused by chronic opioid
exposure [64]. Previous studies have also pointed to opioid receptor downregulation in response to chronic
morphine administration, but in vitro studies have shown an upregulation instead [65]. Amongst all these different
possibilities, the most commonly studied topic surrounds the activation of N-methyl-D-aspartate receptors
(NMDARs) [66]. In chronic pain treatment, the morphine dosages gradually increase, activating NMDARs and
subsequently initiating the secondary messenger system [67]. Another underlying mechanism potentially linking
NMDARs and opioid analgesic tolerance involves protein kinases that regulate the amount of Ca 2+, including
cAMP-dependent protein kinase A (PKA), CaMKII, protein kinase C (PKC), G protein-coupled receptor kinases, or
mitogen-activated protein kinases [68-69]. PKC and CaMKII mediate phosphorylation and contribute to the
development of tolerance when activated [70].
Coupled with the development of receptor desensitization, the upregulation of the cAMP pathway during
chronic opioid exposure leads to increased concentrations of AC, PKA, cAMP response element-binding protein
(CREB), and other signaling molecules [69]. Through this process, opioid upregulation causes neurons to be
intrinsically excited in a parallel reaction, accounting for the expression of opioid tolerance and withdrawal [70-71].
In studies involving the locus coeruleus, opioid use caused opioids to bind to GPCRs, acutely activating G-proteins
[72]. This inherently decreased the neuronal firing rates by inhibiting AC isoforms and activating K + channels [73].
Desensitization occurs when intracellular proteins and signaling molecules like PKA, PKC, and CaMKII are also
activated, both decreasing analgesic activity and increasing CREB expression [72]. When the firing rates return from
their inhibited levels to their pre-treatment levels due to compensatory increases in AC activity and cAMP levels,
tolerance is subsequently developed [74]. The same pattern of upregulation takes place in the NAc [75], VTA [76],
DRN [77], and the periaqueductal gray matter [78], suggesting that these regions may be strongly implicated in drug
abuse disorders. Even though the upregulation of the cAMP pathway is a relatively well-established idea, the exact
mechanisms of how chronic opioid abuse affects it is not fully understood, prompting the need for more research to
be conducted in the field.

6. Opioid-Induced Hyperalgesia

As previously mentioned, opioids are typically prescribed as the standard analgesics to suppress pain
symptoms. Chronic high-dosage opioid use raises many concerns regarding opioid abuse and other adverse effects
associated with it, which is why it is crucial to understand how it causes OIH. As opposed to circumstances under
physiological conditions, increasing the dosage in OIH causes even more pain [79]. The first cases of OIH were
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observed in the 19th century when effects opposite to analgesia occurred in patients who received morphine [10].
Now, studies have been documented in human patients and animal models in which opioid withdrawal caused them
to be increasingly sensitive to external stimuli [80]. Though the specific mechanisms behind OIH have not been
discovered yet, we will discuss the hypotheses that researchers have created to explain this phenomenon that has
affected patients on a widespread scale.
In opioid use signaling, the pronociceptive and antinociceptive pathways become imbalanced, causing
several different mechanisms that may explain the occurrence of OIH [81]. Despite the numerous discrepancies and
controversies regarding the physiological mechanisms, the five most frequently cited hypotheses involve the central
glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and
enhanced nociceptive response [10]. Out of all of these possibilities, the central glutaminergic system has been a
main point of interest. NMDA, an excitatory amino acid similar to glutamate, plays an important role in the
progression of OIH, allodynia, and spontaneous pain [82]. The NMDAR is made up of several subunits (NR1,
NR2A-D, and NR3A/B) that are expressed in different regions of the brain [83]. Current data suggests that when
NMDARs are inhibited by antagonists, the development of both tolerance and OIH can be prevented [ 84].
Following morphine exposure, the NMDARs are excited, most of which is facilitated by the activation of PKC [ 85].
Translocation and/or activation of PKC is initiated by tonic nociceptive afferent input and enhances the excitability
of postsynaptic neurons [86-87]. Similar effects can be observed during the activation of presynaptic NMDARs on
primary afferent fibers, as well as during the extracellular release of nitric oxide [88]. In addition, when the
glutamate transporter (GT) system is inhibited, more glutamate is available to bind to NMDARs [89]. This opens up
the possibility that DBS of the LHb may be able to deplete glutamate transmission, thus inhibiting LHb activity.
The relationship between OIH and tolerance is both extremely complex and interconnected in terms of
mechanisms. A study in which OIH was mediated by NMDARs and the subsequent PKC activation found that after
tolerance was developed with daily morphine injections, the use of both an NMDA antagonist and intracellular PKC
activation was able to induce thermal hyperalgesia. The basis of this argument is that the spinal GTs are
downregulated by chronic morphine administration, leading to the dualistic effects of OIH and tolerance [84]. The
mechanisms behind the spinal GT downregulation are not fully understood, but it is believed that the expression is
regulated by either extracellular glutamate or opioid receptor-mediated intracellular changes involving cAMP.
In the first possibility, morphine inhibits neurotransmitter release, creating a downregulation in the
excitatory amino acid carrier 1 and glutamate/aspartate transporter (GLAST) [85], both of which are vital high-
affinity GTs [90]. On the other hand, cAMP has been seen in cell cultures regulating glutamate transporter 1 and
GLAST expression [91]. Furthermore, NMDARs play a role in mediating the spinal GTs, which was seen when the
noncompetitive NMDAR antagonist MK-801 prevented the development of hyperalgesia potentiated by GT
inhibitor L-trans-pyrrolidine-2-4-dicarboxylate [84]. Another possibility regarding the central glutaminergic system
includes sensitization of spinal neurons controlled by NMDA, leading to enhanced nociception. The duration of
morphine administration also plays a role in the development of OIH, as long-term exposure may cause
neurotoxicity and apoptosis mediated by NMDARs. Chronic opioid exposure may also increase calcitonin gene-
related peptide (CGRP) and substance P in the dorsal root ganglia, both of which are involved in pain transmission
to the brain [92].
Although glutamatergic transmission is currently the most plausible explanation for OIH, researchers have
also investigated the roles of spinal dynorphins and descending facilitation. Spinal dynorphins are a type of opioid
peptides, and when they are infused with MOR agonists, their levels show an overall increase. Subsequently,
excitatory neuropeptides are released, which facilitates pro-nociceptive stimulation [93]. In addition, descending
facilitation increases spinal neuronal responses and has a strong association with chronic pain symptoms, which are
mediated by “on-and-off” cells in the RVM in response to opioids [93-94].

7. Clinical Implications

Despite the significance of this issue, the precise mechanisms behind many of these phenomena, including
opioid tolerance and OIH, remain unknown. For opioid tolerance, the main school of thought is centered around
NMDARs, though researchers uncovered a key flaw by failing to find the source of NMDAR activation during long-
term opioid exposure [95]. The role of receptor desensitization is also a point of contention; while morphine
administration has demonstrated evidence of behavioral tolerance, it has failed to desensitize MORs and has instead
caused AC super sensitization (increases in cAMP levels) [96]. In addition, the lack of clear direction on the exact
mechanisms behind the modulation of opioid antinociceptive tolerance has proven to be a major setback, leading to
a diversity of substances being studied, include CGRP antagonists [97], nitric oxide synthase inhibitors, calcium
channel blockers [98], cyclooxygenase inhibitors, and PKC inhibitors [99]. The wide range of possibilities makes
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the investigation more difficult, especially when multiple systems can have a role in the blocking of opioid
antinociceptive tolerance [95].
Currently, there is an extensive compilation of evidence in nonhuman models that proves OIH to be a real
phenomenon. In human studies, however, there has been a paucity of clinical data to fully clarify the conditions
under which the hyperalgesic effects of opioid doses are expressed [100]. In an alternate perspective, OIH and/or
allodynia are not abnormalities, but rather the body’s way of producing warning signals and behavioral changes that
respond to danger and are associated with the endogenous antinociceptive systems [12]. Rather than looking at OIH
as an adverse effect, it could be part of a bigger picture involving pain sensitization. For instance, after fentanyl (a
common opioid used in surgery) was administered, it not only enhanced carrageenan-induced hyperalgesia, but it
also increased pain sensitivity after the second dosage a week later [101]. This suggests that opioid use itself may
contribute to the underlying neural plasticity behind chronic pain. In general, there are a countless number of
possibilities regarding the presence of OIH and its physiological mechanisms, yet much of it remains uncovered.
As for the future of LHb DBS in the treatment of OIH, overcoming these challenges will come with their
potential benefits. There have been multiple open-label DBS trials held to treat MDD, many of which have had
promising outcomes and have opened up possible areas of improvement. Going forward, there should be a higher
number of participants in the trials, selection of a control, and optimization of the target selection to ensure that there
are no biases, placebo effects, or significant inconsistencies [37]. Because HFS has also typically been required to
achieve effective results in DBS, issues of battery replacement and energy input can be alleviated through the use of
rechargeable batteries in clinical neuropsychiatric settings [102]. Given the success of DBS to treat PD and, more
recently, MDD, it is advisable to approach DBS for OIH in a similar manner and to refine the methodologies based
on the circuits of the disorder itself.
The results of LHb DBS to treat OIH continue to be highly speculative, but much of the previous research
suggests that LHb DBS would be especially effective in treating pain. Extracellular recording of single-unit cells in
rat LHb showed excitatory responses to both noxious and non-noxious stimuli, implying that the LHb is a prime
target for the reception of nociceptive inputs [60]. Because the LHb plays an active role in evaluating somatosensory
inputs, reward signaling, and addiction, it is often described to be part of a main convergence point at which external
stimuli can be processed [103]. Not only was this seen in preclinical trials, but it has also proven relatively
successful in clinical studies; applications of DBS have been used to treat intractable pain for more than 50 years
using various targets and techniques [104]. For instance, in a 15-year study, patients were closely observed after
electrodes for DBS were inserted within the periventricular gray matter, specific sensory thalamic nuclei, or internal
capsule. Select patients achieved long-term pain relief, clarifying certain selection criteria for future treatment and
research using DBS [105].
The efficacy of DBS in treating pain, in combination with the potential of the LHb as a specific target,
implies that LHb DBS may be a promising solution in attenuating OIH. However, at the moment, predictions
continue to be tentative regarding the outcomes of the experimental design. Therefore, a dire push is needed for the
medical community to continue researching the mechanisms of OIH and moving forward with additional clinical
studies.

8. Conclusions

LHb DBS is a novel approach to a technique that has long been used to treat PD, tremors, and other
neuropsychiatric disorders. Due to the LHb’s vital role in aversive, negative reward signaling, it is the main target of
interest in regulating the nociceptive responses to pain sensitivity enhanced by opioid abuse. The abundance of
NMDARs and MORs within the LHb is an indication that it is closely involved with the hypothesized glutamatergic
transmissions and other mechanisms associated with opioid signaling and hyperalgesia. In conjunction with OIH,
the phenomenon of opioid tolerance is thought to be similarly affected by the upregulation of opioid receptors, in
which the precise mechanisms continue to require explication. Even though LHb DBS has not yet been
experimented with to alleviate OIH, the investigations of LHb DBS in neuropsychiatric disorders, such as MDD,
provide a bright outlook for future applications of DBS. As of now, because many of the LHb DBS mechanisms and
effects remain unknown, its therapeutic efficacy in reducing OIH and rescuing OIH-related pathways requires
further study.

Conflicts of Interest: The author reports no conflict of interest in this review.

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