Development Of Opioid Analgesic Tolerance Research Articles

Development of opioid analgesic tolerance in rat to extended-release buprenorphine formulated for laboratory subjects.

Buprenorphine in an extended-release formulation intended for use in laboratory subjects is frequently administered to rats to provide extended analgesia without repeated handling. While levels of buprenorphine may persist in serum once extended-release buprenorphine has been introduced, exposure to opioids can cause opioid tolerance or opioid-induced hypersensitivity. This work examined the analgesic duration and efficacy of a single administration of extended-release buprenorphine intended for use in laboratory subjects in models of inflammatory pain and post-operative pain and the development of opioid tolerance in rat. After subcutaneous administration of 1 mg/kg extended-release buprenorphine, analgesic efficacy did not persist for the expected 72 hours. No changes were observed in mechanical thresholds in the hindpaws that were contralateral to the injury, suggesting a lack of centrally mediated opioid-induced hypersensitivity. To determine whether opioid tolerance arose acutely after one exposure to extended-release buprenorphine, we conducted the warm water tail flick assay; on Day 1 we administered either saline or extended-release buprenorphine (1 mg/kg) and on Day 3 we quantified the standard buprenorphine dose-response curve (0.1-3 mg/kg). Rats previously given extended-release buprenorphine displayed decreased analgesic responses after administration of standard buprenorphine as compared to the robust efficacy of standard buprenorphine in control subjects. Males appeared to show evidence of acute opioid tolerance, while females previously exposed to opioid did not demonstrate a decreased response at the doses examined. Taken together, these results suggest that opioid tolerance arises quickly in male rats after exposure to the extended-release formulation of buprenorphine. This tolerance may account for the brief period of antinociception observed.

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance.

The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B receptor remains a future target for the discovery of drugs to restore opioid efficacy. Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation, which ultimately ends with GluN2B receptor overactivation and glutamate release. The presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor activation. The extrasynaptic localization of the GluN2B receptor means it is influenced by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1). Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence of high glutamate levels or unconventional MOR activation on astrocytes could further activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby reducing opioid tolerance.

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.

The Expression and Function of Nitric Oxide Synthase Enzyme in Atorvastatin Effects on Morphine-Induced Dependence in Mice

Background: Atorvastatin exerts neuroprotective effects on the treatment of central nervous system disorders. Morphine analgesic tolerance and dependence remain as major concerns in medicine. Nitric oxide (NO) pathway mediates the development of opioid analgesic tolerance and dependence, as well as atorvastatin neuroprotection. Objectives: The present study aimed to assess the possible involvement of the NO/cGMP pathway in the process of the effects of atorvastatin on morphine physical dependence. Methods: Dependence was induced by repetitive injection of morphine sulfate. Naloxone was injected at the dose of 4 mg/kg on the last day of the experiment to assess withdrawal signs. Animals received atorvastatin (1, 5, 10, and 20 mg/kg, orally). Nitric oxide synthase (NOS) inhibitors and ODQ were injected before protective dose of atorvastatin. The gene expression of NOS isoforms was evaluated by real-time PCR. Thereafter, the hippocampal levels of cGMP and nitrite were measured. Results: Treatment with atorvastatin 10 mg/kg significantly attenuated naloxone-induced withdrawal behaviours. The administration of L-NAME, aminoguanidine, and ODQ before atorvastatin enhanced its effects. The treatment with atorvastatin significantly decreased the nitrite and cGMP levels as well as NOS gene expression in the hippocampus of dependent animals. Conclusions: It can be concluded that atorvastatin, possibly, through inducible NOS, could alleviate morphine dependence and withdrawal signs.

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice

Oxidative stress and the nitric oxide (NO) pathway are involved in the development of opioid analgesic tolerance and dependence. Simvastatin modulates NO and oxidative stress, so the present study aimed to investigate its effect on the development and expression of morphine analgesic tolerance and withdrawal signs in mice. Morphine tolerance and dependence were induced by twice daily morphine injection (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was assessed by the hot-plate test and dependence by naloxone challenge, on the sixth day. To determine if the NO is involved in the effects of simvastatin, mice were pre-treated with l-arginine (200 mg/kg) or the NO synthesis inhibitors (L-NAME; 30 mg/kg) along with simvastatin (300 mg/kg). The results showed that acute and chronic administration of simvastatin reversed the antinociceptive tolerance of morphine and attenuated withdrawal signs in morphine-dependent mice, and this effect is reversed by l-arginine and augmented by l-NAME. Also, the concentration of NO and oxidative stress factors such as malondialdehyde content, total thiol, and glutathione peroxidase (GPx) activity in brain tissues was evaluated. Chronic administration of simvastatin reduced NO and malondialdehyde, and increased total thiol and GPx levels in the cerebral cortex and hippocampus of morphine-dependent mice which were antagonized by l-arginine, and augmented by l-NAME. In summary, simvastatin attenuates morphine-induced antinociceptive tolerance and withdrawal symptoms, at least partly, through antioxidative properties and nitric oxide pathway.

Methylnaltrexone crosses the blood-brain barrier and attenuates centrally-mediated behavioral effects of morphine and oxycodone in mice

BackgroundAntagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice. MethodsCombinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry. ResultsMNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier. ConclusionsThese results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.

Effect of heat shock protein 70 modulators on the development of morphine analgesic tolerance in rats.

The clinical use of opioid analgesics, such as morphine, is limited by analgesic tolerance, molecular mechanism of which is not well understood. Recently, molecular chaperone heat shock protein 70 (Hsp70) has been demonstrated to play important roles in morphine-induced neuroadaptation. Here, we focused on the involvement of Hsp70 in the development of analgesic tolerance to morphine. Rats were treated with morphine (5, 10, 20 mg/kg, subcutaneously) or saline once daily for 10 consecutive days. Hsp70 modulator N-formyl-3, 4-methylenedioxybenzylidine-γ-butyrolactam [KNK437, 100 mg/kg, intraperitoneally (i.p.)], geranylgeranylacetone (500 mg/kg, i.p.) or pifithrin-μ (20 mg/kg, i.p.) was administered before morphine (10 mg/kg, subcutaneously)/saline treatment. Analgesic effect of morphine was measured using the tail-flick latency test, and Hsp70 protein expression was examined by western blot. Analgesic effect of morphine decreased gradually with the increase in the number of days of morphine injection, indicating development of analgesic tolerance. A significant increase of Hsp70 expression in the periaqueductal gray was observed during the development of analgesic tolerance after repeated morphine injections. The development of morphine analgesic tolerance was suppressed by pre-treatment with Hsp70 transcriptional inhibitor KNK437 or functional antagonist pifithrin-μ, while promoted by pre-treatment with Hsp70 transcriptional inducer geranylgeranylacetone. Our results demonstrated that the development of morphine analgesic tolerance was dual regulated by Hsp70 modulators, suggesting Hsp70 as an interesting and new target for preventing the development of opioid analgesic tolerance.

Inhibition of HINT1 Modulates Spinal Nociception and NMDA Evoked Behavior in Mice.

The interactions between the mu-opioid (MOR) and N-methyl-d-aspartate receptor (NMDAR) constitute an area of intense investigation because of their contributions to maladaptive neuroplasticity. Recent evidence suggests that their association requires the involvement of histidine triad nucleotide-binding protein (HINT1) with the enzyme's active site being critical in its regulatory role. Since it is known that spinal blockade of NMDA receptors prevents the development of opioid analgesic tolerance, we hypothesized that spinal inhibition of the HINT1 enzyme may similarly inhibit opioid tolerance. To address these questions, we evaluated novel HINT1 active-site inhibitors in two models of NMDAR and MOR interaction, namely, MOR inhibition of spinal NMDA activation and acute endomorphin-2 tolerance. These studies revealed that while the tryptamine carbamate of guanosine inhibitor, TrpGc, blocked both the development of opioid tolerance and the inhibitory effect of opioids on NMDA activation of the NMDA receptor, acyl-sulfamate analogues could only block the latter. Thermodynamic binding and X-ray crystallographic studies suggested that there are key differences between the bound HINT1-inhibitor surfaces that may be responsible for their differential ability to probe the ability of HINT1 to regulate cross talk between the mu-opioid receptor and NMDA receptor in the spinal cord.

Venlafaxine prevents morphine antinociceptive tolerance: The role of neuroinflammation and the l-arginine-nitric oxide pathway

Opioid-induced neuroinflammation and the nitric oxide (NO) signal-transduction pathway are involved in the development of opioid analgesic tolerance. The antidepressant venlafaxine (VLF) modulates NO in nervous tissues, and so we investigated its effect on induced tolerance to morphine, neuroinflammation, and oxidative stress in mice. Tolerance to the analgesic effects of morphine were induced by injecting mice with morphine (50 mg/kg) once a day for three consecutive days; the effect of co-administration of VLF (5 or 40 mg/kg) with morphine was similarly tested in a separate group. To determine if the NO precursor l-arginine hydrochloride (l-arg) or NO are involved in the effects rendered by VLF, animals were pre-treated with l-arg (200 mg/kg), or the NO synthesis inhibitors N(ω)-nitro-l-arginine methyl ester (L-NAME; 30 mg/kg) or aminoguanidine hydrochloride (AG; 100 mg/kg), along with VLF (40 mg/kg) for three days before receiving morphine for another three days. Nociception was assessed with a hot-plate test on the fourth day, and the concentration of tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), interleukin-10, brain-derived neurotrophic factor, NO, and oxidative stress factors such as total thiol, malondialdehyde content, and glutathione peroxidase (GPx) activity in the brain was also determined. Co-administration of VLF with morphine attenuated morphine-induced analgesic tolerance and prevented the upregulation of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), NO, and malondialdehyde in brains of mice with induced morphine tolerance; chronic VLF administration inhibited this decrease in brain-derived neurotrophic factor, total thiol, and GPx levels. Moreover, repeated administration of l-arg before receipt of VLF antagonized the effects induced by VLF, while L-NAME and AG potentiated these effects. VLF attenuates morphine-induced analgesic tolerance, at least partly because of its anti-inflammatory and antioxidative properties. VLF also appears to suppress the development of morphine-induced analgesic tolerance through an l-arg–NO-mediated mechanism.

Current gene therapy using viral vectors for chronic pain.

The complexity of chronic pain and the challenges of pharmacotherapy highlight the importance of development of new approaches to pain management. Gene therapy approaches may be complementary to pharmacotherapy for several advantages. Gene therapy strategies may target specific chronic pain mechanisms in a tissue-specific manner. The present collection of articles features distinct gene therapy approaches targeting specific mechanisms identified as important in the specific pain conditions. Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery. Dr. Tao group addresses that downregulation of a voltage-gated potassium channel (Kv1.2) contributes to the maintenance of neuropathic pain. Alleviation of chronic pain through restoring Kv1.2 expression in sensory neurons is presented in this review. Drs Goins and Kinchington group describes a strategy to use the replication defective HSV vector to deliver two different gene products (enkephalin and TNF soluble receptor) for the treatment of post-herpetic neuralgia. Dr. Hao group addresses the observation that the pro-inflammatory cytokines are an important shared mechanism underlying both neuropathic pain and the development of opioid analgesic tolerance and withdrawal. The use of gene therapy strategies to enhance expression of the anti-pro-inflammatory cytokines is summarized. Development of multiple gene therapy strategies may have the benefit of targeting specific pathologies associated with distinct chronic pain conditions (by Guest Editors, Drs. C. Fairbanks and S. Hao).

Involvement of Moesin in the Development of Morphine Analgesic Tolerance through P-glycoprotein at the Blood-Brain Barrier

Altered expression of P-glycoprotein (P-gp), a drug efflux transporter expressed by brain capillary endothelial cells (BCECs), may contribute to the development of opioid analgesic tolerance, as demonstrated by cumulative evidence from research. However, the detailed mechanism by which chronic morphine treatment increases P-gp expression remains unexplained. Ezrin/radixin/moesin (ERM) are scaffold proteins that are known to regulate the plasma membrane localization of some drug transporters such as P-gp in peripheral tissues, although a few reports suggest its role in the central nervous system as well. In this study, we investigated the involvement of ERM in the development of morphine analgesic tolerance through altered P-gp expression in BCECs. Repeated treatment with morphine (10 mg/kg/day, s.c. for 5 days) decreased its analgesic effect in the tail-flick test and increased P-gp protein expression in BCECs, as determined by Western blotting. Furthermore, moesin protein expression increased in the same fraction whereas that of ezrin decreased; no change was observed in the radixin expression. Furthermore, immunoprecipitation and immunofluorescence assays revealed interaction between moesin and P-gp molecules, along with co-localization, in BCECs. In conclusion, an increase in moesin expression may contribute to the increased expression of P-gp in BCECs, leading to the development of morphine analgesic tolerance.

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Attenuation of opioid analgesic tolerance in p75 neurotrophin receptor null mutant mice

Repeated exposure to opioid drugs can lead to the development of tolerance, which manifests as a reduction in analgesic potency, and physical dependence, a response indicated by a withdrawal syndrome. Accumulating evidence suggests that the nerve growth factor (NGF) family of neurotrophins may have an important modulatory role in the induction of opioid analgesia and opioid addiction. Because neurotrophins universally bind the p75 neurotrophin receptor (p75NTR), we investigated whether the activity of this receptor is involved in the development of opioid analgesic tolerance and physical dependence. We found that in both the wild-type and p75NTR−/− mice an acute systemic (i.p.) injection of morphine produced a maximal analgesic response as measured by the thermal tail-immersion test. Repeated injection of morphine over 5 days in wild-type mice resulted in a progressive decline of the analgesic effect and a concomitant loss of the agonist potency, reflecting development of morphine tolerance. However, the loss of morphine analgesia was not observed in p75NTR−/− mice. In the second part of this study, mice were given escalating doses of systemic (i.p.) morphine over 5 days and subsequently challenged with the opioid receptor antagonist naloxone. This challenge precipitated a robust withdrawal syndrome that was comparable in wild-type mice and p75NTR−/− mice. The findings suggest that p75NTR activity plays a critical role in the development of opioid analgesic tolerance but not in the induction or the expression of opioid physical dependence.

Resistance to morphine analgesic tolerance in rats with deleted transient receptor potential vanilloid type 1-expressing sensory neurons

Deletion of transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons reduces presynaptic μ opioid receptors but paradoxically potentiates the analgesic efficacy of μ opioid agonists. In this study, we determined if removal of TRPV1-expressing afferent neurons by resiniferatoxin (RTX), an ultrapotent capsaicin analog, influences the development of opioid analgesic tolerance. Morphine tolerance was induced by daily intrathecal injections of 10 μg of morphine for 14 consecutive days or by daily i.p. injections of 10 mg/kg of morphine for 10 days. In vehicle-treated rats, the effect of intrathecal or systemic morphine on the mechanical withdrawal threshold was gradually diminished within 7 days. However, the analgesic effect of intrathecal and systemic morphine was sustained in RTX-treated rats at the time the morphine effect was lost in the vehicle group. Furthermore, the μ opioid receptor-G protein coupling in the spinal cord was significantly decreased (∼22%) in vehicle-treated morphine tolerant rats, but was not significantly altered in RTX-treated rats receiving the same treatment with morphine. Additionally, there was a large reduction in protein kinase Cγ-immunoreactive afferent terminals in the spinal dorsal horn of RTX-treated rats. These findings suggest that loss of TRPV1-expressing sensory neurons attenuates the development of morphine analgesic tolerance possibly by reducing μ opioid receptor desensitization through protein kinase Cγ in the spinal cord. These data also suggest that the function of presynaptic μ opioid receptors on TRPV1-expressing sensory neurons is particularly sensitive to down-regulation by μ opioid agonists during opioid tolerance development.

Evidence for a role of CaMKIV in the development of opioid analgesic tolerance

cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the micro-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the micro-opioid receptor than did wild-type mice, while uncoupling was similar in control wild-type and KO mice. In addition, morphine reduced inhibitory transmission to a greater degree in CaMKIV-KO mice than in controls after chronic morphine exposure. Our results provide novel evidence for the role of CaMKIV in the development of opioid analgesic tolerance but not physical dependence.

Involvement of spinal lipoxygenase metabolites in hyperalgesia and opioid tolerance

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB 4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3 R-hydroxy-1 E,5 Z-undecadien-1-yl)-2-pyridinyl)-1,5 S-hexanediol (U75302), a leukotriene BLT receptor antagonist. Treatment with 15-hydroxyperoxyeicosatetranoic acid (HPETE) increased phase II formalin activity, but had no effect on tail-flick responses. 12-HPETE failed to produce an effect in either nociceptive test. In the second part of this study, chronic spinal morphine for 5 days produced progressive decline in morphine antinociception and loss in analgesic potency. These effects were attenuated by co-administration of morphine with selective and nonselective lipoxygenase inhibitors. These results suggest involvement of lipoxygenase metabolites in both pain modulation and induction of opioid tolerance at the spinal level.