Development Of Analgesic Tolerance Research Articles

Intravenous administration of recombinant Phα1β: Antinociceptive properties and morphine tolerance reversal in a cancer-associated pain model

Cancer-related pain is considered one of the most prevalent symptoms for those affected by cancer, significantly influencing quality of life and treatment outcomes. Morphine is currently employed for analgesic treatment in this case, however, chronic use of this opioid is limited by the development of analgesic tolerance and adverse effects, such as digestive and neurological disorders. Alternative therapies, such as ion channel blockade, are explored. The toxin Phα1β has demonstrated efficacy in blocking calcium channels, making it a potential candidate for alleviating cancer-related pain. This study aims to assess the antinociceptive effects resulting from intravenous administration of the recombinant form of Phα1β (r-Phα1β) in an experimental model of cancer-related pain in mice, tolerant or not to morphine. The model of cancer-induced pain was used to evaluate these effects, with the injection of B16F10 cells, followed by the administration of the r-Phα1β, and evaluation of the mechanical threshold by the von Frey test. Also, adverse effects were assessed using a score scale, the rotarod, and open field tests. Results indicate that the administration of r-Phα1β provoked antinociception in animals with cancer-induced mechanical hyperalgesia, with or without morphine tolerance. Previous administration of r-Phα1β was able to recover the analgesic activity of morphine in animals tolerant to this opioid. r-Phα1β was proved safe for these parameters, as no adverse effects related to motor and behavioral activity were observed following intravenous administration. This study suggests that the concomitant use of morphine and r-Phα1β could be a viable strategy for pain modulation in cancer patients.

CYP2D in the brain alters the development of analgesic tolerance and behavioral sensitization to repeated oral oxycodone

CYP2D in the brain alters the development of analgesic tolerance and behavioral sensitization to repeated oral oxycodone

Adeno-associated virus-mediated gene transfer of arginine decarboxylase to the central nervous system prevents opioid analgesic tolerance.

Agmatine, a decarboxylated form of L-arginine, prevents opioid analgesic tolerance, dependence, and self-administration when given by both central and systemic routes of administration. Endogenous agmatine has been previously detected in the central nervous system. The presence of a biochemical pathway for agmatine synthesis offers the opportunity for site-specific overexpression of the presumptive synthetic enzyme for local therapeutic effects. In the present study, we evaluated the development of opioid analgesic tolerance in ICR-CD1 mice pre-treated with either vehicle control or intrathecally delivered adeno-associated viral vectors (AAV) carrying the gene for human arginine decarboxylase (hADC). Vehicle-treated or AAV-hADC-treated mice were each further divided into two groups which received repeated delivery over three days of either saline or systemically-delivered morphine intended to induce opioid analgesic tolerance. Morphine analgesic dose-response curves were constructed in all subjects on day four using the warm water tail flick assay as the dependent measure. We observed that pre-treatment with AAV-hADC prevented the development of analgesic tolerance to morphine. Peripheral and central nervous system tissues were collected and analyzed for presence of hADC mRNA. In a similar experiment, AAV-hADC pre-treatment prevented the development of analgesic tolerance to a high dose of the opioid neuropeptide endomorphin-2. Intrathecal delivery of anti-agmatine IgG (but not normal IgG) reversed the inhibition of endomorphin-2 analgesic tolerance in AAV-hADC-treated mice. To summarize, we report here the effects of AAV-mediated gene transfer of human ADC (hADC) in models of opioid-induced analgesic tolerance. This study suggests that gene therapy may contribute to reducing opioid analgesic tolerance.

Assessing effects of tamoxifen on tolerance, dependence, and glutamate and glutamine levels in frontal cortex and hippocampus in chronic morphine treatment

Tamoxifen has been shown to reduce glutamate release from presynaptic glutamatergic nerves and reverse tolerance to morphine-induced respiratory depression. Changes in glutamatergic neurotransmission in the central nervous system contribute to morphine tolerance, dependence, and withdrawal. This study, therefore, evaluated effects of tamoxifen on development of analgesic tolerance and dependence, and brain glutamate and glutamine levels in chronic morphine administration. Mice implanted with placebo or morphine pellets were injected with tamoxifen (0.6–2 mg/kg) or vehicle twice daily for 3 days. Nociceptive response was evaluated in the hot plate and tail immersion tests, 4, 48 and 72 h post-implant, and following a challenge dose of morphine (10 mg/kg). Withdrawal signs were determined after naloxone (1 mg/kg) administration. Morphine increased nociceptive threshold which declined over time. At 72 h, acute morphine elicited tolerance to the analgesic effect in the hot plate test in vehicle or tamoxifen administered animals. In the tail immersion test, however, tolerance to morphine analgesia was observed in tamoxifen, but not vehicle, co-administration. Tamoxifen did not reduce withdrawal signs. In contrast to previous reports, glutamate and glutamine levels in the hippocampus and frontal cortex did not change in the morphine-vehicle group. Confirming previous findings, tamoxifen (2 mg/kg) decreased glutamate and glutamine concentrations in the hippocampus in animals with placebo pellets. Both doses of tamoxifen significantly changed glutamate and/or glutamine concentrations in both regions in morphine pellet implanted animals. These results suggest that tamoxifen has no effect on dependence but may facilitate tolerance development to the antinociception, possibly mediated at the spinal level, in chronic morphine administration.

Evaluation of Analgesic Tolerance Induced by Metamizole in the Writhing Test Model

Analgesic tolerance is defined as the need for increasing doses to achieve the intended effect. In this paper we present experimental data from the search for analgesic tolerance induced by metamizole in a pain model induced by 0.9% acetic acid known as abdominal constriction test or Writhing test. The aim of this study was to identify the development of analgesic tolerance to metamizole in the Writhing test model. Experimental: groups of Balb/C mice 6±2 were used. They were administered metamizole in different protocols, and subsequently underwent a pain stimulus with 0.9% acetic acid via intraperitoneal, evaluated for 30 minutes and counting time of latency, number of abdominal stretches in order to rate pain response, subsequently naloxone was administered to look for signs of withdrawal. Our results demonstrated that there is a tendency to develop analgesic tolerance to metamizole after its repeated administration.

The role of the gut microbiome and microbial metabolism in mediating opioid-induced changes in the epigenome.

The current opioid pandemic is a major public health crisis in the United States, affecting millions of people and imposing significant health and socioeconomic burdens. Preclinical and clinical research over the past few decades has delineated certain molecular mechanisms and identified various genetic, epigenetic, and environmental factors responsible for the pathophysiology and comorbidities associated with opioid use. Opioid use-induced epigenetic modifications have been identified as one of the important factors that mediate genetic changes in brain regions that control reward and drug-seeking behavior and are also implicated in the development of tolerance. Recently, it has been shown that opioid use results in microbial dysbiosis, leading to gut barrier disruption, which drives systemic inflammation, impacting the perception of pain, the development of analgesic tolerance, and behavioral outcomes. In this review, we highlight the potential role of microbiota and microbial metabolites in mediating the epigenetic modifications induced by opioid use.

Chronic Morphine Modulates PDGFR-β and PDGF-B Expression and Distribution in Dorsal Root Ganglia and Spinal Cord in Male Rats

The analgesic effect of opioids decreases over time due to the development of analgesic tolerance. We have shown that inhibition of the platelet-derived growth factor beta (PDGFR-β) signaling eliminates morphine analgesic tolerance in rats. Although the PDGFR-β and its ligand, the platelet-derived growth factor type B (PDGF-B), are expressed in the substantia gelatinosa of the spinal cord (SG) and in the dorsal root ganglia (DRG), their precise distribution within different cell types of these structures is unknown. Additionally, the impact of a tolerance-mediating chronic morphine treatment, on the expression and distribution of PDGF-B and PDGFR-β has not yet been studied. Using immunohistochemistry (IHC), we found that in the spinal cord, PDGFR-β and PDGF-B were expressed in neurons and oligodendrocytes and co-localized with the mu-opioid receptor (MOPr) in opioid naïve rats. PDGF-B was also found in microglia and astrocytes. Both PDGFR-β and PDGF-B were detected in DRG neurons but not in spinal primary afferent terminals. Chronic morphine exposure did not change the cellular distribution of PDGFR-β or PDGF-B. However, PDGFR-β expression was downregulated in the SG and upregulated in the DRG. Consistent with our previous finding that morphine caused tolerance by inducing PDGF-B release, PDGF-B was upregulated in the spinal cord. We also found that chronic morphine exposure caused a spinal proliferation of oligodendrocytes. The changes in PDGFR-β and PDGF-B expression induced by chronic morphine treatment suggest potential mechanistic substrates underlying opioid tolerance.

Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model.

Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing N-methyl-d-Aspartate receptors is thought to play a key role in mechanisms underlying cellular adaptation that takes place in the development of analgesic tolerance. Herein, we describe a novel GluN2B-selective negative allosteric modulator, EU93-108, that shows high potency and brain penetrance. We describe the structural basis for binding at atomic resolution. This compound possesses intrinsic analgesic properties in the rodent tail immersion test. EU93-108 has an acute and significant anodyne effect, whereby morphine when combined with EU93-108 produces a higher tail flick latency compared to that of morphine alone. These data suggest that engagement of GluN2B as a target has utility in the treatment of pain, and EU93-108 could serve as an appropriate tool compound to interrogate this hypothesis. Future structure-activity relationship work around this scaffold could give rise to compounds that can be co-administered with opioids to diminish the onset of tolerance due to chronic opioid use, thereby modifying their utility.

Comparative investigation of analgesic tolerance to taurine, sodium salicylate and morphine: Involvement of peripheral muscarinic receptors

Nowadays various analgesic medications are used for the management of acute and chronic pain. Among these opioid and non-steroidal anti-inflammatory drugs stand in the first line of therapy, however, prolonged administration of these substance is generally challenged by development of analgesic tolerance in patients. Therefore, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. In this respect, Taurine, a free amino acid, has been shown to induce significant analgesia at both spinal and peripheral levels through cholinergic mechanisms. In the present study, we used hot-plate analgesic test to investigate how taurine either as a single medication or in combination with sodium salicylate and morphine may affect both acute response to pain and development of analgesic tolerance. The effect of taurine was also tested on morphine withdrawal syndrome. Hyoscine butyl bromide was used to assess the role of muscarinic receptors in taurine-mediated effects. Finally, biochemical assay was done to reveal how the activity of brain acetylcholinesterase may change in relation with muscarinic receptor activity. Results indicated that acute administration of taurine-sodium salicylate combination causes more potent analgesia compared to the use of tau (but not SS alone) and this seems to be mediated via activity of muscarinic receptors in peripheral nervous system. Furthermore, the effect of this combination undergoes less analgesic tolerance during time. Combination of taurine and morphine is an effective strategy to attenuate both morphine analgesic tolerance and dependence and this also seems to depend on activity of muscarinic receptors, however through differential cellular mechanisms.

Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice.

Opioid Use Disorder (OUD) affects approximately 8%-12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone-treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid-induced analgesia.

δ-Opioid receptors in primary sensory neurons tonically restrain nociceptive input in chronic pain but do not enhance morphine analgesic tolerance

δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest that DORs promote the development of analgesic tolerance of μ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance. In this study, we generated Oprd1 conditional knockout (Oprd1-cKO) mice by crossing Advillin-Cre mice with Oprd1-floxed mice. DOR expression in the dorsal root ganglion was diminished in Oprd1-cKO mice. Systemic or intrathecal injection of the DOR agonist SNC-80 produced analgesia in wild-type (WT), but not Oprd1-cKO, mice. In contrast, intracerebroventricular injection of SNC-80 produced a similar analgesic effect in WT and Oprd1-cKO mice. However, morphine-induced analgesia, hyperalgesia, or analgesic tolerance did not differ between WT and Oprd1-cKO mice. Compared with WT mice, Oprd1-cKO mice showed increased mechanical and heat hypersensitivity after nerve injury or tissue inflammation. Furthermore, blocking DORs with naltrindole increased nociceptive sensitivity induced by nerve injury or tissue inflammation in WT, but not Oprd1-cKO, mice. In addition, naltrindole potentiated glutamatergic input from primary afferents to spinal dorsal horn neurons increased by nerve injury or CFA in WT mice; this effect was absent in Oprd1-cKO mice. Our findings indicate that DORs in primary sensory neurons are critically involved in the analgesic effect of DOR agonists but not morphine-induced analgesic tolerance. Presynaptic DORs at primary afferent central terminals constitutively inhibit inflammatory and neuropathic pain by restraining glutamatergic input to spinal dorsal horn neurons.

Characterization of Novel, Agmatine‐Based NMDA Receptor Antagonists in Multiple Pain States

The worsening opioid epidemic has highlighted the need for the development of new, safe, and effective analgesic therapeutics. Opioid therapy currently is associated with the risk of conversion to addiction, diversion from patients for whom use is intended, and the development of analgesic tolerance, or the loss of efficacy with continued treatment. To this end, we have developed a line of non‐opioid, agmatine‐based compounds and assessed them for their efficacy in reversing behavioral expressions of pain in animal models, as well as evaluated their safety following chronic exposure. We have previously shown that agmatine, decarboxylated L‐arginine, is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that preferentially antagonizes receptors that express NR2B subunits. This preferential antagonism is desirable for NMDA‐based therapeutics as it can lead to a widening of the therapeutic window and avoidance of the side effects commonly associated with NMDA antagonism including motor ataxia and psychoactive effects. However, agmatine has shown limited penetration through the blood brain barrier (BBB) and a short systemic half‐life, limiting its clinical utility. We have designed strategically‐substituted agmatine (SSA) compounds with the goal of improving its penetration through the BBB by increasing the lipophilicity of agmatine, potentially improving distribution across the BBB and increasing its half‐life following systemic delivery. To this end, we have evaluated this series of SSAs for safety and efficacy in multiple animal models of pain.Mice (21‐30 g, M/F) were assessed for their baseline mechanical sensitivity, and then one of several models of pain was induced: inflammatory pain (Complete Freund’s Adjuvant, (CFA) injected into a hindpaw), neuropathic pain (spared nerve injury surgery), or post‐surgical pain (hindpaw muscle incision). Mechanical sensitivity was again assessed, then an SSA compound, agmatine (the parent compound), or vehicle control was administered, and mechanical sensitivity was recorded for up to three hours following administration. The SSA compounds effectively reversed pain behaviors in mice following administration in the various pain models. Additionally, side effects characteristic of NMDA receptor antagonists were assessed and not found at the range of doses that produced analgesia, indicating a wide therapeutic window.These data indicate that the strategically‐substituted agmatines are anti‐hyperalgesic compounds with a wide therapeutic window, avoiding the motor impairment typical of drugs of this class.

AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression

BackgroundThe development of morphine tolerance is a clinical challenge for managing severe pain. Studies have shown that neuroinflammation is a critical aspect for the development of analgesic tolerance. We found that AMPK-autophagy activation could suppress neuroinflammation and improve morphine tolerance via the upregulation of suppressor of cytokine signaling 3 (SOCS3) by inhibiting the processing and maturation of microRNA-30a-5p.MethodsCD-1 mice were utilized for the tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of AMPK-autophagy-mediated posttranscriptional regulation of SOCS3. Proinflammatory cytokines were measured by western blotting and real-time PCR. The levels of SOCS3 and miRNA-processing enzymes were evaluated by western blotting, real-time PCR and immunofluorescence staining.ResultsBased on experimental verification, miRNA-30a-5p could negatively regulate SOCS3. The AMPK activators AICAR, resveratrol and metformin downregulated miRNA-30a-5p. We found that AMPK activators specifically inhibited the processing and maturation of miRNA-30a-5p in microglia by degrading DICER and AGO2 via autophagy. Furthermore, a miRNA-30a-5p inhibitor significantly improved morphine tolerance via upregulation of SCOS3 in mice. It markedly increased the level of SOCS3 in the spinal cord of mice and subsequently inhibited morphine-induced phosphorylation of NF-κB p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1β and TNF-α caused by morphine in microglia.ConclusionAMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p.

The Guts of the Opioid Crisis.

Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.

Agonist dependency of the second phase access of \u03b2-arrestin 2 to the heteromeric \xb5-V1b receptor

During the development of analgesic tolerance to morphine, the V1b vasopressin receptor has been proposed to bind to β-arrestin 2 and the µ-opioid receptor to enable their interaction. However, direct evidence of such a high-order complex is lacking. Using bioluminescent resonance energy transfer between a split Nanoluciferase and the Venus fluorescent protein, the NanoBit-NanoBRET system, we found that β-arrestin 2 closely located near the heteromer µ-V1b receptor in the absence of an agonist and moved closer to the receptor carboxyl-termini upon agonist stimulation. An additive effect of the two agonists for opioid and vasopressin receptors was detected on the NanoBRET between the µ-V1b heteromer and β-arrestin 2. To increase the agonist response of NanoBRET, the ratio of the donor luminophore to the acceptor fluorophore was decreased to the detection limit of luminescence. In the first phase of access, β-arrestin 2 was likely to bind to the unstimulated V1b receptor in both its phosphorylated and unphosphorylated forms. In contrast, the second-phase access of β-arrestin 2 was agonist dependent, indicating a possible pharmacological intervention strategy. Therefore, our efficient method should be useful for evaluating chemicals that directly target the vasopressin binding site in the µ-V1b heteromer to reduce the second-phase access of β-arrestin 2 and thereby to alleviate tolerance to morphine analgesia.

Pharmacological and genetic manipulations at the \xb5-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice

Opioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.

Establishment of an Individualized Chronotherapy, Autonomic Nervous System, and Variability-Based Dynamic Platform for Overcoming the Loss of Response to Analgesics

Control of chronic pain and mainly the partial or complete loss of response to analgesics is a major unmet need. Multiple mechanisms underline the development of tolerance to analgesics in general and specifically to opioids. The autonomic nervous system (ANS) plays a role in the development of analgesic tolerance and chronobiology. To review the mechanisms associated with the development of nonresponsiveness to analgesics. Literature review. The review is followed by a description of a new method for overcoming resistance and improving the response to analgesics. Conducted a detailed review of the relevant studies describing the mechanisms that underlie tolerance to pain medications, and the potential roles of the ANS and chronobiology in the development of drug resistance. The autonomic balance is reflected by heart rate variability, an example of a fundamental variability that characterizes biological systems. Chronotherapy, which is based on the circadian rhythm, can improve the efficacy and reduce the toxicity of chronic medications. In this article, we present the establishment of an individualized variability- and chronobiology-based therapy for overcoming the compensatory mechanisms associated with a loss of response to analgesics. We describe the premise of implementing personalized signatures associated with the ANS, and chronobiology, as well as with the pathophysiology of pain for establishing an adaptive model that could improve the efficacy of opioids, in a highly dynamic system. The studies presented were selected based on their relevance to the subject. The described variability-based system may ensure prolonged effects of analgesics while reducing the toxicity associated with increasing dosages.

Synthesis of the Mechanisms of Opioid Tolerance: Do We Still Say NO?

The use of morphine as a first-line agent for moderate-to-severe pain is limited by the development of analgesic tolerance. Initially opioid receptor desensitization in response to repeated stimulation, thought to underpin the establishment of tolerance, was linked to a compensatory increase in adenylate cyclase responsiveness. The subsequent demonstration of cross-talk between N-methyl-D-aspartate (NMDA) glutamate receptors and opioid receptors led to the recognition of a role for nitric oxide (NO), wherein blockade of NO synthesis could prevent tolerance developing. Investigations of the link between NO levels and opioid receptor desensitization implicated a number of events including kinase recruitment and peroxynitrite-mediated protein regulation. Recent experimental advances and the identification of new cellular constituents have expanded the potential signaling candidates to include unexpected, intermediary compounds not previously linked to this process such as zinc, histidine triad nucleotide-binding protein 1 (HINT1), micro-ribonucleic acid (mi-RNA) and regulator of G protein signaling Z (RGSZ). A further complication is a lack of consistency in the protocols used to create tolerance, with some using acute methods measured in minutes to hours and others using days. There is also an emphasis on the cellular changes that are extant only after tolerance has been established. Although a review of the literature demonstrates a lack of spatio-temporal detail, there still appears to be a pivotal role for nitric oxide, as well as both intracellular and intercellular cross-talk. The use of more consistent approaches to verify these underlying mechanism(s) could provide an avenue for targeted drug development to rescue opioid efficacy.

Pain, negative affective states and opioid-based analgesics: Safer pain therapies to dampen addiction.

Across centuries and civilizations opioids have been used to relieve pain. In our modern societies, opioid-based analgesics remain one of the most efficient treatments for acute pain. However, the long-term use of opioids can lead to the development of analgesic tolerance, opioid-induced hyperalgesia, opioid use disorders, and overdose, which can ultimately produce respiratory depressant effects with fatal consequences. In addition to the nociceptive sensory component of pain, negative affective states arising from persistent pain represent a risk factor for developing an opioid use disorder. Several studies have indicated that the increase in prescribed opioid analgesics since the 1990s represents the root of our current opioid epidemic. In this review, we will present our current knowledge on the endogenous opioid system within the pain neuroaxis and the plastic changes occurring in this system that may underlie the occurrence of pain-induced negative affect leading to misuse and abuse of opioid medications. Dissecting the allostatic neuronal changes occurring during pain is the most promising avenue to uncover novel targets for the development of safer pain medications. We will discuss this along with current and potential approaches to treat pain-induced negative affective states that lead to drug misuse. Moreover, this chapter will provide a discussion on potential avenues to reduce the abuse potential of new analgesic drugs and highlight a basis for future research and drug development based on recent advances in this field.

Analgesic Tolerance Development during Repetitive Electric Stimulations Is Associated with Changes in the Expression of Activated Microglia in Rats with Osteoarthritis.

Electric stimulation is used for managing osteoarthritic (OA) pain; however, little is known about the development of analgesic tolerance during repeated stimulations and the relation of spinal microglia with OA pain. We investigated the changes in the analgesic effects of repeated electric stimulations and the relation between the development of analgesic tolerance and spinal microglial expression in rats with OA. To induce OA, monosodium iodoacetate was injected into the synovial space of the right knee joint of the rats (n = 185). Repeated high frequency, low frequency, or sham transcutaneous electric nerve stimulation (TENS) was performed to the ipsilateral knee joint for 20 min in rats with OA (n = 45). Minocycline or minocycline plus TENS (HF, LF, or sham) was treated in OA rats with repeated TENS-induced tolerance (n = 135). Immunohistochemistry of the microglia in the L3–L5 spinal segments was performed. Knee joint pain during passive movement of the knee joint were quantified using the knee-bend score and the proportion of activated microglia was calculated as primary variables. Paw withdrawal threshold (hypersensitivity to mechanical stimuli) was assessed and the resting and activated microglia were counted as secondary variables. Repeated applications decreased the analgesic effect of TENS on OA pain and failed to reduce the expression of activated microglia in the spinal cord. However, spinal microglial inhibition by minocycline restored the analgesic effect of TENS on OA pain in TENS-tolerant OA rats. TENS combined with minocycline treatment improved knee joint pain and mechanical hypersensitivity in TENS-tolerant OA rats, and inhibited the expression of activated microglia in the spinal cord. These results suggest a possible relationship between repetitive electric stimulation-induced analgesic tolerance for OA pain control and changes in microglia activation.