Opioid receptors: structure, subtypes, and function

Opioid receptors belong to the G protein-coupled receptor (GPCR) family, a class of transmembrane proteins that initiate intracellular signaling cascades upon activation. When an opioid receptor is engaged by a ligand, it triggers a signaling pathway involving increased cyclic adenosine monophosphate (cAMP) production and activation of protein kinase A (PKA). This leads to downstream modulation—either activation or inhibition—of various proteins, enzymes, and ion channels.

Opioid receptors are widely distributed throughout the central and peripheral nervous systems. They are also expressed on non-neuronal tissues, including immune cells.

Five major opioid receptor subtypes have been described: the mu-opioid receptor (MOR), kappa-opioid receptor (KOR), delta-opioid receptor (DOR), nociceptin/orphanin FQ receptor (NOR), and the more recently identified zeta-opioid receptor (ZOR).

The best-characterized receptors—MOR, KOR, and DOR—are naloxone-sensitive and mediate classical opioid effects such as analgesia, respiratory depression, euphoria, and dependence. Among these, MOR plays a central role in both analgesic and immunomodulatory actions. Evidence from MOR knockout (MORKO) mouse models demonstrates that morphine fails to suppress immune pathways in the absence of MOR, establishing its necessity for opioid-induced immunosuppression [1, 6, 7].

NOR, a naloxone-insensitive opioid receptor, is found in the limbic system and appears to be involved in the regulation of opioid tolerance. NOR and its endogenous ligand, nociceptin/orphanin FQ (N/OFQ), are expressed in both the central nervous system (CNS) and peripheral immune cells at comparable levels, suggesting a potential role for NOR as a key mediator in neuroimmune interaction and brain-immune axis regulation.

Clinically elevated NOR-related messenger ribonucleic acid (mRNA) expression has been observed in intensive care unit (ICU) patients with advanced cancer, sepsis, and major surgery, correlating with increased mortality [8].

ZOR, the zeta-opioid receptor, has been implicated in tissue growth and repair [6, 9, 10], though no definitive role in immune modulation has yet been established.

Opioid receptor expression in immune cells

Opioid receptors are expressed on a wide range of immune cells, including macrophages, lymphocytes, and dendritic cells. Activation of these receptors by exogenous opioids modulates key immune functions—altering cell proliferation, cytokine secretion, chemotaxis, and phagocytic activity [1, 6]. Endogenous opioid peptides, such as endorphins and enkephalins, also interact with these receptors and contribute to immune regulation [11].

Direct cellular and cytokine-mediated effects

Direct opioid signaling in immune cells suppresses key effector functions. Morphine has been shown to suppress NK cell activity, impair macrophage phagocytic function, and inhibit lymphocyte proliferation, thereby weakening the host’s initial immune defense mechanisms [1, 6, 13].

Upon activation, opioid receptors modulate intracellular signaling cascades involving adenylate cyclase, cAMP, mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB), which are pivotal in regulating immune gene expression. Additionally, opioids influence cytokine production, typically downregulating pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), while promoting anti-inflammatory mediators such as transforming growth factor-beta (TGF-β) and IL-10 [5, 13, 14]. This shift in cytokine profiles compromises pathogen clearance and may promote immune dysregulation [1, 5].

Indirect neuroendocrine and autonomic pathways

Opioids influence immune function indirectly through their actions on the CNS. By binding to opioid receptors expressed in the CNS, morphine activates the HPA axis, leading to the release of glucocorticoids and catecholamines, stress hormones with potent immunosuppressive properties [7, 13, 15, 16].

Glucocorticoid effects on immunity are complex: They suppress T helper type 1 (Th1)-mediated cellular immunity, promote T helper type 2 (Th2) responses, impair dendritic cell maturation, and expand IL-10-producing regulatory T cells [7, 17].

Morphine-induced activation of the sympathetic nervous system further suppresses immune function via catecholamines and various neuropeptides. Catecholamines inhibit NK cell activity and alter lymphocyte function [7]. Neuropeptides—such as substance P, somatostatin, and vasoactive intestinal peptide—bind to high-affinity receptors on lymphocytes, eliciting distinct immunomodulatory effects [18].

Although specific pathways remain under debate [6], the convergence of direct and indirect mechanisms accounts for the immunosuppressive phenotype observed with many opioids.

Opioid-mediated dysregulation of innate host defense

Innate immunity provides a rapid, non-specific barrier against invading pathogens. Opioids disrupt several key components of this first line of defense by engaging MORs expressed on various immune cells, including neutrophils, macrophages, mast cells, NK cells, and dendritic cells [1, 2, 4]. In macrophages, morphine has been shown to impair proliferation, reduce phagocytic capacity and migration, and diminish bactericidal activity, while neutrophil recruitment to the sites of bacterial infection is similarly inhibited [4, 12, 19].

Additionally, morphine reduces mast cell activation, leading to increased intestinal permeability and thereby facilitating microbial translocation and infection [4, 12, 19].

The impact of opioids on macrophages appears to be dose-dependent: At low to moderate doses, morphine impairs phagocytic capacity, whereas higher doses can trigger macrophage apoptosis via TLR9 signaling and activation of the p38-MAPK pathway [4].

Collectively, these disruptions weaken the innate immune competence and heighten susceptibility to a broad spectrum of pathogens, including HIV, hepatitis C, and influenza [6, 20]. The cumulative effect is a compromised first-line defense that leaves the opioid-exposed host more vulnerable to both acute and chronic infections.

Opioid modulation of adaptive immunity

The adaptive immune system orchestrates highly specific responses and immunological memory through coordinated interactions among T cells, B cells, and antigen-presenting cells (APCs) such as macrophages and dendritic cells. Within this network, opioids exert complex and predominantly suppressive effects.

Chronic opioid use has been associated with impaired T- and B-cell function, including reduced T helper cell proliferation and diminished antibody production by B cells [1, 6]. Opioid exposure has also been shown to alter T-cell differentiation and to impair memory T-cell formation, further weakening adaptive defense mechanisms [2, 4, 20].

Morphine, in particular, has been found to decrease the expression of major histocompatibility complex class II (MHC-II) molecules on B cells by approximately 33%. This reduction constrains antigen presentation, thereby impairing T-cell activation and the coordination of the adaptive immune response [19]. These effects are believed to be partly mediated through activation of the HPA axis and the sympathetic nervous system, which elevate corticosteroid levels—known potent mediators of immunosuppression [21, 22].

At the cytokine level, morphine promotes an anti-inflammatory milieu characterized by increased TGF-β and IL-10 and reduced IL-2, IL-1β, TNF-α, and IFN-γ [23].

Concurrently, it skews T helper differentiation toward a Th2 phenotype, favoring humoral immunity while attenuating Th1-mediated cellular immune responses [24].

Although advantageous in certain contexts (e.g., parasitic defense and allergy), this Th2 bias compromises host resistance to intracellular pathogens, including viruses and many bacteria [24].

Together, these effects illustrate how opioids, particularly when used chronically, can undermine the adaptive immune system’s capacity to respond effectively to infections, vaccines, and other immunological challenges.

Morphine

Morphine is a prototypical immunosuppressive opioid, affecting both innate and adaptive arms of immunity [1, 6, 12, 25]. It promotes microbial translocation and inflammatory injury within the gastrointestinal tract, further exacerbating systemic immune dysfunction [13].

In a retrospective study on patients with cancer receiving either morphine or oxycodone, infections occurred significantly more often in the morphine-treated group. Acknowledging the study limitations, the authors proposed that morphine’s immunosuppressive profile may contribute to heightened infection risk in this population [29]. These findings align with broader evidence that morphine suppresses key cellular components of innate and adaptive immunity and is associated with increased risk of postoperative complications [12, 13, 27].

The effect of morphine on tumor biology is complex and context-dependent. In some preclinical models, morphine can enhance tumor proliferation, invasiveness, and angiogenesis, potentially facilitating tumor progression under certain conditions. Conversely, other studies show that morphine can induce apoptosis and inhibit angiogenesis, indicating possible tumor-inhibitory effects. These divergent outcomes, shaped by cancer type, dose, timing, and experimental conditions, preclude a unified conclusion regarding morphine’s net impact on tumor growth [27].

Fentanyl

Fentanyl appears to share many of morphine’s immunosuppressive properties, though its profile is less extensively studied. Available data support dose-dependent suppression of NK cell activity, lymphocyte multiplication, and cytokine release [6, 25]. In animal models, chronic fentanyl administration is associated with the development of tolerance not only to analgesia but also to its immunosuppressive effects. Notably, tolerance to immunosuppression may emerge earlier than tolerance to analgesia, both outcomes being influenced by the dose and duration of exposure.

Human studies, largely in perioperative cohorts or healthy volunteers, similarly report reductions in NK cell activity and levels, diminished CD8⁺ cytotoxic T cells, and decreased cytokine production [25, 30].

By contrast, patients with cancer pain or individuals using fentanyl illicitly remain underrepresented in current research. Robust, long-term studies in these populations are needed to clarify fentanyl’s sustained immunological consequences.

Oxycodone

Oxycodone is a semi-synthetic opioid and a relatively selective full MOR agonist, with moderate-to-high MOR affinity—though lower than that of morphine and fentanyl—and weaker binding to DORs and KORs. Oxycodone and its active metabolite, oxymorphone, readily cross the blood-brain barrier, exerting direct effects on CNS. Despite extensive clinical use, the immunological profile of oxycodone is not fully delineated.

Animal studies suggest that oxycodone is less immunosuppressive than morphine [25]. In male mice, repeated oxycodone administration has been reported to suppress immune function while upregulating TLR4 and NF-κB mRNA expression in T cells, suggesting potential pro-inflammatory and/or immunosuppressive effects that may depend on dose and exposure duration [31].

In human studies, oxycodone has been associated with milder and more transient immunosuppressive effects compared with morphine and fentanyl [25, 29].

Overall, current evidence suggests that oxycodone may have a comparatively favorable immunomodulatory profile among commonly used MOR agonists, although further research is needed to fully define its immune effects.

Methadone

Methadone is a synthetic opioid with a multifaceted pharmacology: It functions primarily as a MOR agonist, with weaker activity at KOR and DOR, and additionally acts as a weak N-methyl-D-aspartate (NMDA) receptor antagonist. This NMDA component may influence both analgesia and tolerance development.

Animal and human studies indicate that methadone exerts mild immunosuppressive effects, including reduced NK cell activity, impaired macrophage function, and diminished antibody production—generally less pronounced than with morphine or fentanyl. Much of the clinical immunomodulatory effects of methadone have been examined in the context of opioid use disorder (OUD) maintenance therapy.

In heroin-dependent individuals, methadone-assisted detoxification has been shown to restore aspects of cellular immunity compromised by chronic heroin use. Dendritic cell populations (myeloid and plasmacytoid subsets) and Human leukocyte antigen-DR isotype (HLA-DR) expression, which are significantly reduced in these individuals, partially recover following methadone treatment [32].

Overall, multiple studies report improvements in immune function among individuals on methadone maintenance therapy. However, it remains uncertain to what extent these benefits are attributable to direct pharmacologic effects of methadone versus broader health gains associated with cessation of illicit opioid use [25].

Buprenorphine

Buprenorphine displays a unique and complex receptor profile, acting as a high-affinity partial MOR agonist, a partial agonist/antagonist at KOR, an antagonist at DOR, and a weak partial NOR agonist. This receptor diversity likely underpins its distinct pharmacological and immunological effects.

Buprenorphine generally exhibits minimal immunosuppressive activity.

Several studies report neutral or even protective, immunostimulatory effects, suggesting potential advantages in immunocompromised settings. In animal studies, buprenorphine—unlike morphine and fentanyl—did not impair NK cell, T cell, or macrophage function [25].

In clinical settings, individuals with OUD maintained on buprenorphine show significant improvements in immune markers following the initiation of treatment. Existing research suggests that opioid-induced peripheral immune suppression may be reversible with buprenorphine therapy [33]. These observations raise the possibility that buprenorphine not only avoids further immune compromise but may contribute to restoration of immune homeostasis.

To date, converging preclinical and clinical evidence suggests that buprenorphine has little to no detrimental impact on immune function, positioning it as a particularly attractive option for analgesia and maintenance therapy when immune preservation is a priority [25, 34, 35]

Tramadol

Tramadol is a centrally acting analgesic with a dual mechanism of action: weak MOR agonism and inhibition of serotonin and norepinephrine reuptake. Its main active metabolite, O-desmethyltramadol (M1), displays higher MOR affinity than the parent compound. This combined opioid and monoaminergic activity shapes a distinct immunomodulatory profile compared with conventional MOR agonists.

Animal and human studies indicate that tramadol and M1 exert minimal immunosuppressive effects—significantly less than those observed with morphine [26]. In fact, data suggest that tramadol may enhance certain immune functions under specific conditions, including increased NK cell cytotoxicity, augmented phagocytosis, enhanced lymphocyte proliferation, and elevated IL-2 production. These immunostimulatory actions are largely attributed to tramadol’s serotonergic properties, consistent with broader evidence that serotonin and norepinephrine play important roles in immune regulation [14, 25, 26, 36].

Multiple preclinical and clinical comparisons demonstrate that tramadol preserves immune function, often in direct contrast to other opioids, particularly morphine [26]. In perioperative settings, tramadol has been shown to counteract surgery-induced suppression of NK cell activity and lymphocyte proliferation, suggesting a protective role during acute physiological stress [37].

Tramadol’s minimal or absent immunosuppressive effects likely reflect its low MOR affinity. Its capacity to preserve—or even stimulate—immune responses makes it a compelling analgesic choice in clinical scenarios where maintaining immune competence is critical.

Susceptibility to infections

The interaction between opioid use, immune dysregulation, and infection gained heightened attention in the 1980s, when the concurrent epidemics of heroin use and HIV/AIDS were accompanied by high rates of opportunistic infections. In this setting, overlapping drivers of immune impairment—including HIV infection, chronic opioid use, and recurrent infections—created a synergistic vulnerability associated with worse clinical outcomes and increased mortality.

In humans, prolonged opioid use has been linked to an increased incidence of a wide range of infections, including bacterial skin and soft tissue infections, respiratory and urinary tract infections, as well as endovascular and musculoskeletal infections [1, 4, 6, 11, 38]. The risk is particularly elevated among intravenous opioid users, where both pharmacologically induced immunosuppression and non-sterile injection practices contribute to heightened vulnerability. In the context of HIV-1 (Human Immunodeficiency Virus type 1) infection, opioids appear to further potentiate immune dysfunction, exacerbating HIV-1 pathogenesis and increasing susceptibility to additional opportunistic viral and bacterial infections [39].

Studies in hospitalized patients with sepsis have shown that chronic opioid use is associated with increased mortality compared to opioid-naive individuals [40, 41]. Premorbid opioid therapy has been independently associated with reduced survival following ICU admission [40]. Consistent with experimental and clinical data on opioid-associated immunosuppression, patients receiving long-term opioid therapy demonstrate a higher incidence of positive microbiological cultures across gram-positive, gram-negative, and fungal pathogens. Additionally, chronic opioid use is known to compromise intestinal barrier function, promoting bacterial translocation and systemic infection [41].

Collectively, these findings suggest that chronic opioid use prior to critical illness may weaken host defenses and increase susceptibility to infection, thereby worsening clinical outcomes.

A retrospective ten-year cohort analysis demonstrated that initiation of long-acting opioids with known immunosuppressive properties (e.g., morphine, fentanyl, and methadone) was associated with higher infection rates among hospitalized patients, with the greatest risk observed within the first 30 days of therapy [42].

Additional insight into opioid-induced immune disruption comes from patients with inflammatory bowel disease (IBD). In this population, prolonged opioid administration has been associated with gut microbiome dysbiosis, characterized by pathogenic bacterial overgrowth and enhanced microbial translocation. These changes disrupt immune homeostasis, propagate chronic inflammation, and may contribute to systemic infectious complications [13, 43].

In conclusion, these observations underscore the need to systematically assess infection risk when considering long-term opioid therapy, especially in patients with pre-existing immune compromise, gastrointestinal pathology, or critical illness, where even modest immune perturbations can precipitate serious—and potentially fatal—infectious events.

Cancer progression

Patients with malignancy represent a particularly vulnerable group in whom opioid-induced immunosuppression may influence disease trajectory. Although opioids remain essential for the management of cancer-related pain, their potential to impair anti-tumor immunity has become a growing concern, especially as immunotherapies become increasingly important in cancer treatment.

In addition to immunomodulation via the MOR, opioids can activate TLR4 and trigger pro-inflammatory signaling cascades. These dual and sometimes opposing actions highlight the complex, bidirectional nature of opioid-immune interactions.

In vitro data indicate that exposure of human NK cells to various opioids can suppress their cytotoxic activity against leukemia cell targets, though the magnitude of this effect differs across agents [12]. Notably, fentanyl, M1, and [D-Pen², D-Pen⁵] enkephalin did not impair NK cell function in these models. Beyond sparing NK function in vitro, fentanyl has been reported to inhibit invasion and progression of human colorectal cancer cells, likely via downregulation of miR-182 and MMP-9 expression through β-catenin signaling pathways [44, 45].

The suppression of NK cell function observed with other opioids appears to be mediated primarily through MOR and KOR. Buprenorphine, methadone, and tramadol have all been implicated in NK cell inhibition [30]. This direct suppression of NK activity, in conjunction with additional indirect mechanisms, may contribute to the association between perioperative opioid exposure and increased cancer recurrence [30, 44].

Preclinical models further support the potential for opioids to influence tumor biology. Animal studies have shown that morphine can promote tumor neovascularization, growth, and metastasis [6, 13, 27]. In a transgenic mouse model of breast cancer, Nguyen et al. [46] reported that opioids enhanced tumor progression when administered after tumor establishment, whereas pre-tumor exposure did not have the same effect, suggesting that timing and disease stage may modulate opioid-tumor interactions.

Human data regarding opioid use and cancer risk or progression remain mixed and are confounded by underlying indications for opioid therapy.

A 2022 cohort study using propensity score matching and multivariate Cox regression analysis found that long-term opioid use was associated with an increased risk of several malignancies, including gastric, breast, colorectal, prostate, ovarian, pancreatic, lung, head and neck, esophageal, and liver cancers [47]. The authors proposed several potential mechanisms—immune dysregulation, post-opioid chromosomal damage, enhanced neovascularization and angiogenesis, pharmacologic interactions with carcinogens, and organ dysfunction leading to prolonged carcinogen exposure—but emphasized the need for confirmatory studies.

Emerging evidence suggests that opioids may facilitate cancer progression less through direct oncogenic effects and more by suppressing immune surveillance and promoting angiogenesis [12, 13, 20]. Through MOR- and TLR4-mediated pathways, opioids modulate immune and inflammatory responses, suppress NK cell activity, alter T- and B- cell function, reduce antibody production, and dampen cytokine release. This broad immunosuppression may compromise the host’s capacity to mount an effective anti-tumor response and reduce micrometastatic expansion, potentially impacting disease progression and the effectiveness of immunotherapies [2, 15, 25, 30]. Ultimately, opioid-associated effects on cancer outcomes may be driven predominantly by alterations in host immunity rather than direct tumor cell targeting [15].

Cancer patients often exist in a state of fragile immune equilibrium. Opioid therapy is only one of many factors that influence this balance. The malignancy itself, cancer treatments, organ dysfunction, malnutrition, pain, and psychological stress all contribute to immune compromise. Uncontrolled pain and suffering can independently impair immune function and overall health, and may in some cases be more detrimental than the immunologic effects of appropriately used opioids [48].

These considerations underscore the importance of carefully balancing effective pain control with the potential risks of opioid-induced immune modulation, particularly in patients receiving immunotherapies or undergoing curative-intent treatment. Striking this balance should remain a central focus in comprehensive oncologic care.

Impact on surgical outcomes

In patients undergoing major surgery, immune competence is challenged by both the underlying disease process and the physiological stress of the operative procedure. Pain itself, together with immune-modulating mediators released at the site of tissue injury, further destabilizes this fragile immunologic balance [11, 35]. Opioids are routinely administered for perioperative analgesia; however, their immunosuppressive effects may exacerbate immune dysfunction during this critical period.

Data from animal and human investigations indicate that both acute and chronic opioid administration can suppress NK cell activity, inhibit lymphocyte proliferation, and attenuate cytokine production—effects that may impair wound healing and increase the risk of postoperative infection [2, 11, 35]. Observational clinical studies further associate chronic preoperative opioid use with higher rates of postoperative infections, including pneumonia and serious surgical site or deep organ/space infections [4].

These concerns are amplified in oncologic surgery, where immune competence plays a pivotal role in controlling residual disease and limiting metastatic dissemination. Patients with preexisting immune compromise—such as those with chronic systemic illnesses, malnutrition, or concurrent immunosuppressive therapies—may be particularly susceptible to complications, prolonged recovery, and worsening of overall prognosis when exposed to immunosuppressive doses of opioids.

Given the converging immunosuppressive effects of surgery, pain, and opioid administration, careful evaluation of analgesic strategies is essential in high-risk surgical populations. Multimodal analgesia, incorporating non-opioid pharmacologic agents, regional anesthesia techniques, and non-pharmacologic modalities, can reduce systemic opioid requirements and may help preserve perioperative immune function.

Implications for transplant recipients

Transplant recipients, who rely on a tightly calibrated immunosuppression to maintain graft function while preserving host defense, represent a population in whom additional opioid-induced immune modulation may be particularly consequential. Direct data in this group remain limited, but insights can be extrapolated from perioperative, oncology, and critical care literature.

Preclinical and clinical studies show that morphine can markedly depress NK cell activity and inhibit T-cell proliferation—processes that are central to both immune surveillance and graft tolerance. Opioid-induced suppression of NK cells, macrophages, and T cells, along with inhibition of key cytokines, has been implicated in delayed graft acceptance, diminished graft survival, and increased infection risk, ultimately contributing to higher morbidity and mortality [49, 50].

These effects are especially concerning in solid organ transplant (SOT) recipients, where any additional immune perturbation can shift the balance toward either rejection or uncontrolled infection.

A systematic review of opioid use in SOT recipients and living donors identified chronic pre-transplant opioid use as an independent predictor of adverse post-transplant outcomes, including increased risk of graft loss and death [49]. Although mechanistic pathways were not delineated in that review, other studies suggest that opioid-induced reductions in NK cell numbers and activity may predispose to infections and post-transplant malignancies [50]. Infection remains a leading cause of death among SOT patients [51], and a recent study by Søborg et al. [52] reported that infectious complications were the most frequent cause of death during the first year after transplantation. Opioid-associated impairment of gut barrier integrity, neutrophil dysfunction, and cytokine suppression further heighten vulnerability to opportunistic infections in this context.

For transplant recipients, whose management depends on maintaining an optimal equilibrium between immunosuppression and host defense, opioid therapy has the potential to shift this balance toward harmful immune suppression. Judicious opioid use, preference for agents with more favorable immunologic profiles when feasible, and integration of multimodal analgesic strategies may help mitigate these risks.

Implications for opioid tolerance

Opioid tolerance arises from interconnected processes within the CNS and the peripheral immune system. Although the mechanistic landscape is complex and not yet fully understood, opioid-induced neuroinflammation—shaped by dynamic crosstalk between central and peripheral immune signals—has emerged as a key contributor [9].

Within the CNS, opioids activate glial cells, particularly microglia and astrocytes, via MOR as well as pattern recognition receptors such as TLR4. TLRs recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR4, in particular, detects endotoxins like lipopolysaccharide (LPS) and activates pro-inflammatory signaling cascades that overlap with IL-1β pathways [53, 54].

Opioid-mediated MOR activation can potentiate glial responses to LPS, amplifying neuroinflammation. The resulting release of inflammatory mediators sensitizes nociceptive neurons, increases their excitability, diminishes opioid analgesic efficacy, accelerates tolerance, and may promote opioid-induced hyperalgesia. In a self-augmentation pattern, injured or sensitized neurons release signals that further activate glial cells and perpetuate neuroinflammatory cascades [9]. At the receptor level, tolerance is driven by MOR desensitization and downregulation, engagement of β-arrestins and regulators of G-protein signaling (RGS) proteins, and compensatory upregulation of excitatory neurotransmission, including NMDA/glutamate pathways.

While CNS glial cells are central to these processes, the role of the peripheral immune system in initiating and sustaining central immune signaling is increasingly recognized. Peripheral inflammatory signals can access the CNS via circulating cytokines and immune-derived mediators, including blood-borne IL-1β-containing vesicles and neutrophil-derived microparticles, which in turn activate microglia and reinforce neuroinflammation [9, 55, 56].

Peripherally, opioid-induced immunosuppression predominates; however, the net immune effect can differ by drug, dose, and exposure duration, and pro-inflammatory actions have been observed under specific conditions.

Given this intricate bidirectional communication, strategies to mitigate opioid tolerance may benefit from targeting both central and peripheral immune mechanisms. Potential approaches include inhibition of TLR4 signaling, blockade of pro-inflammatory cytokines such as TNF-α and IL‐1β, and modulation of peripheral immune pathways that drive CNS glial activation.