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Drug addiction is a chronic and debilitating disease that is considered a global health problem. Various cell types in the brain are involved in the progression of drug addiction. Recently, the xenobiotic hypothesis has been proposed, which frames substances of abuse as exogenous molecules that are responded to by the immune system as foreign “invaders”, thus triggering protective inflammatory responses. An emerging body of literature reveals that microglia, the primary resident immune cells in the brain, play an important role in the progression of addiction. Repeated cycles of drug administration cause a progressive, persistent induction of neuroinflammation by releasing microglial proinflammatory cytokines and their metabolic products. This contributes to drug addiction via modulation of neuronal function. In this review, we focus on the role of microglia in the etiology of drug addiction. Then, we discuss the dynamic states of microglia and the correlative and causal evidence linking microglia to drug addiction. Finally, possible mechanisms of how microglia sense drug-related stimuli and modulate the addiction state and how microglia-targeted anti-inflammation therapies affect addiction are reviewed. Understanding the role of microglia in drug addiction may help develop new treatment strategies to fight this devastating societal challenge.

Key Points Pain processing involves neurons, microglia and astrocytes. The functions of glia extend beyond basic support for neurons. Once activated, they release various classic immune factors that are also neuroactive substances. Glia express receptors for neurotransmitters and neuromodulators, so they can respond to neural activity. Despite the integral part that glia play in neuronal communication, most of the drugs that are available for treating pathological pain in humans target neuronal mechanisms. This may be one reason for their limited therapeutic efficacy in pain control. Early evidence from preclinical studies with animal models of neuropathic pain suggest that shifting glial activation from a pro-inflammatory to an anti-inflammatory state may prove to be important in clinical pain phenomena. Activated glia exert crucial neuroprotective and anti-inflammatory effects. Identifying ways to regulate the switch between the proinflammatory and the anti-inflammatory state of glial activation, rather than simply blocking glial actions, could be key to the development of more powerful strategies to treat clinical pain. Activated glia exert both positive and negative effects on pain processing. Milligan and Watkins review the molecular mechanisms that underlie neuron–glia interactions in this context. Manipulation of these interactions could represent a new and more efficient approach to treating chronic pain. Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, anti-inflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron–glia interactions in pain processing hold considerable promise.

Key Points Local and recruited immunocompetent cells (such as microglia, astrocytes, endothelial cells, perivascular macrophages and T cells) in the central nervous system (CNS) detect neurotransmitters, chemokines and endogenous danger signals that are released by lesioned or diseased sensory neurons. Immunocompetent cells in the central nervous system subsequently release cytokines, chemokines, prostaglandins, neurotrophic factors and reactive oxygen species that dysregulate synaptic transmission leading to amplification of nociceptive signalling. Other facets of the immune response to neuronal lesion and disease are gaining recognition, including the necessity of pro-inflammatory mediators for repair, and regulation of pro-inflammatory responses by anti-inflammatory mediators. Hence, the most successful treatment approaches targeting the immune system will probably integrate basic science understanding of nuanced immune responses. Despite there being only indirect evidence for a CNS immune component to chronic pain in humans, immune-targeted therapies are showing early signs of success in treating such pain. Here, the authors describe the immune mechanisms that are involved in pain, one of the key features of inflammation. They explain how the immune and nervous systems interact to initiate and propagate pain, and discuss the immune components that can be targeted for alleviating pathological pain in patients. Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs — which focus on suppressing aberrant neuronal activity — new strategies to manipulate neuroimmune pain transmission hold considerable promise.

Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain—namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent “two-hit hypothesis” of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.

Key Points Presently available drugs are ineffective in controlling clinical pain in most patients and abolish the pain in only few. It is suggested that this failure arises from the fact that these drugs were developed to target neurons, rather than spinal cord glia (astrocytes and microglia). Until recently, glia were thought of simply as housekeepers for neurons, regulating the extracellular ionic environment and removing debris. Recently, it has become recognized that these glia dynamically modulate the function of neurons under both physiological and pathological conditions. Glial activation has been demonstrated to be both necessary and sufficient for enhanced nociception (pain transmission) in every animal model tested to date. Activated glia enhance pain via the release of a variety of neuroactive substances. Central to these effects is glial release of pro-inflammatory cytokines (tumor-necrosis factor, interleukin-1 (IL-1) and IL-6). These, in turn, activate a cascade of events leading to the release of a host of neuroexcitatory substances (such as nitric oxide, prostaglandins, growth factors, excitatory amino acids and so on). In animal models, the following block/reverse changes in nociception in every animal model of clinical pain studied to date: disruption of glial activation (fluorocitrate and minocycline); pro-inflammatory cytokine antagonists (Kineret, Remicade, Enbrel); pro-inflammatory cytokine synthesis inhibitors (propentofylline, thalidomide); and disrupting pro-inflammatory cytokine signalling and synthesis (leflunomide, methotrexate, p38 MAP kinase, IL-10). These studies strongly indicate that drug discovery should seriously consider targeting spinal cord glial activation as a broad-spectrum solution to presently unresolved clinical pain syndromes. In many clinical pain syndromes, painful sensations are greatly amplified so that normally innocuous sensations, such as light touch or warmth, are perceived as pain. Presently available drugs are ineffective in controlling such pain in most patients and abolish the pain in only few. Why do they fail? These drugs were developed to target neurons that transmit nociceptive ('pain') information. However, glia have recently been recognized as powerful modulators of nociception, and could hold the key to the control of clinical pain and present a new target for drug discovery. This review examines the evidence for glial regulation of nociception and pharmacological approaches that might successfully control glially driven clinical pain syndromes.

Rationale Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration of TLR4 antagonists provides mixed evidence that TLR4 contributes to cocaine reward and reinforcement. Objective These studies utilize (+)-naltrexone, the TLR4 antagonist, and mu-opioid inactive enantiomer to examine the role of TLR4 on cocaine self-administration and cocaine seeking in rats. Methods (+)-Naltrexone was continuously administered via an osmotic mini-pump during the acquisition or maintenance of cocaine self-administration. The motivation to acquire cocaine was assessed using a progressive ratio schedule following either continuous and acute (+)-naltrexone administration. The effects of (+)-naltrexone on cocaine seeking were assessed using both a cue craving model and a drug-primed reinstatement model. The highly selective TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides (LPS-Rs), was administered into the nucleus accumbens to determine the effectiveness of TLR4 blockade on cocaine-primed reinstatement. Results (+)-Naltrexone administration did not alter the acquisition or maintenance of cocaine self-administration. Similarly, (+)-naltrexone was ineffective at altering the progressive ratio responding. Continuous administration of (+)-naltrexone during forced abstinence did not impact cued cocaine seeking. Acute systemic administration of (+)-naltrexone dose-dependently decreased cocaine-primed reinstatement of previously extinguished cocaine seeking, and administration of LPS-Rs into the nucleus accumbens shell also reduced cocaine-primed reinstatement of cocaine seeking. Discussion These results complement previous studies suggesting that the TLR4 plays a role in cocaine-primed reinstatement of cocaine seeking, but may have a more limited role in cocaine reinforcement.

Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.