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Background and Purpose: In rodents, morphine antinociception is influenced by sex. However, conflicting results have been reported regarding the interaction between sex and morphine antinociceptive tolerance. Morphine is metabolised in the liver and brain into morphine‐3‐glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might contribute to behavioural discrepancies. This article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice. Experimental Approach Sex differences in morphine antinociception and tolerance were assessed using the tail‐immersion test. After acute and chronic morphine treatment, morphine and M3G metabolic kinetics in the blood were evaluated using LC‐MS/MS. They were also quantified in several CNS regions. Finally, the blood–brain barrier (BBB) permeability of M3G was assessed in male and female mice. Key Results: This study demonstrated that female mice showed weaker morphine antinociception and faster induction of tolerance than males. Additionally, female mice showed higher levels of M3G in the blood and in several pain‐related CNS regions than male mice, whereas lower levels of morphine were observed in these regions. M3G brain/blood ratios after injection of M3G indicated no sex differences in M3G BBB permeability, and these ratios were lower than those obtained after injection of morphine. Conclusion: These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain‐related CNS regions, consistent with weaker morphine antinociceptive effects in females. However, the role of morphine metabolism in antinociceptive tolerance seemed limited. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

Analgesic tolerance is a major problem in the clinic for the maintenance of opioid-induced long-term pain relief. Opioids with mixed activity on multiple opioid receptors promise reduced antinociceptive tolerance in preclinical studies, but these compounds typically show poor bioavailability upon oral, subcutaneous, intraperitoneal, or intravenous administration. We designed UTA1003 as a novel opioid that acts as a mu (MOP) and kappa (KOP) opioid receptor agonist and a partial agonist for delta (DOP) opioid receptor. In the present study, its antinociceptive effects, as well as its effects on antinociceptive tolerance and motor behaviour, were investigated in male rats. Acute antinociception was measured before (basal) and at different time points after subcutaneous injection of UTA1003 or morphine using the tail flick and hot plate assays. Various motor behavioural activities, including horizontal locomotion, rearing, and turning, were automatically measured in an open-field arena. The antinociceptive and behavioural effects of repeated administration of UTA1003 and morphine were determined over eight days. UTA1003 induced mild antinociceptive effects after acute administration but induced no tolerance after repeated treatment. Importantly, UTA1003 co-treatment with morphine prevented antinociceptive tolerance compared to morphine alone. UTA1003 showed less motor suppression than morphine in both acute and sub-chronic treatment regimens, while it did not affect morphine-induced motor suppression or hyper-excitation. Based on these activities, we speculate that UTA1003 crosses the blood-brain barrier after subcutaneous administration and, therefore, could be developed as a lead molecule to avoid opioid-induced antinociceptive tolerance and motor suppression. Further structural modifications to improve its antinociceptive effects, toxicity profile, and ADME parameters are nevertheless required. [ABSTRACT FROM AUTHOR]

Acutely, non-selective cannabinoid (CB) agonists have been shown to increase morphine antinociceptive effects, and we and others have also demonstrated that non-selective CB agonists attenuate morphine antinociceptive tolerance. Activation of cannabinoid CB2 receptors reverses allodynia and hyperalgesia in models of chronic pain, and co-administration of morphine with CB2 receptor selective agonists has been shown to be synergistic. CB2 receptor activation has also been shown to reduce morphine-induced hyperalgesia in rodents, an effect attributed to CB2 receptor modulation of inflammation. In the present set of experiments, we tested both the acute and chronic interactions between morphine and the CB2 receptor selective agonist O-1966 treatments on antinociception and antinociceptive tolerance in C57Bl6 mice. Co-administration of morphine and O-1966 was tested under three dosing regimens: simultaneous administration, morphine pre-treated with O-1966, and O-1966 pre-treated with morphine. The effects of O-1966 on mu-opioid receptor binding were determined using [3H]DAMGO and [35S]GTPγS binding assays, and these interactions were further examined by FRET analysis linked to flow cytometry. Results yielded surprising evidence of interactions between the CB2 receptor selective agonist O-1966 and morphine that were dependent upon the order of administration. When O-1966 was administered prior to or simultaneous with morphine, morphine antinociception was attenuated and antinociceptive tolerance was exacerbated. When O-1966 was administered following morphine, morphine antinociception was not affected and antinociceptive tolerance was attenuated. The [35S]GTPγS results suggest that O-1966 interrupts functional activity of morphine at the mu-opioid receptor, leading to decreased potency of morphine to produce acute thermal antinociceptive effects and potentiation of morphine antinociceptive tolerance. However, O-1966 administered after morphine blocked morphine hyperalgesia and led to an attenuation of morphine tolerance, perhaps due to well-documented anti-inflammatory effects of CB2 receptor agonism. [ABSTRACT FROM AUTHOR]

Acutely, non-selective cannabinoid (CB) agonists have been shown to increase morphine antinociceptive effects, and we and others have also demonstrated that non-selective CB agonists attenuate morphine antinociceptive tolerance. Activation of cannabinoid CB2 receptors reverses allodynia and hyperalgesia in models of chronic pain, and co-administration of morphine with CB2 receptor selective agonists has been shown to be synergistic. CB2 receptor activation has also been shown to reduce morphine-induced hyperalgesia in rodents, an effect attributed to CB2 receptor modulation of inflammation. In the present set of experiments, we tested both the acute and chronic interactions between morphine and the CB2 receptor selective agonist O-1966 treatments on antinociception and antinociceptive tolerance in C57Bl6 mice. Co-administration of morphine and O-1966 was tested under three dosing regimens: simultaneous administration, morphine pre-treated with O-1966, and O-1966 pre-treated with morphine. The effects of O-1966 on mu-opioid receptor binding were determined using [3H]DAMGO and [35S]GTPγS binding assays, and these interactions were further examined by FRET analysis linked to flow cytometry. Results yielded surprising evidence of interactions between the CB2 receptor selective agonist O-1966 and morphine that were dependent upon the order of administration. When O-1966 was administered prior to or simultaneous with morphine, morphine antinociception was attenuated and antinociceptive tolerance was exacerbated. When O-1966 was administered following morphine, morphine antinociception was not affected and antinociceptive tolerance was attenuated. The [35S]GTPγS results suggest that O-1966 interrupts functional activity of morphine at the mu-opioid receptor, leading to decreased potency of morphine to produce acute thermal antinociceptive effects and potentiation of morphine antinociceptive tolerance. However, O-1966 administered after morphine blocked morphine hyperalgesia and led to an attenuation of morphine tolerance, perhaps due to well-documented anti-inflammatory effects of CB2 receptor agonism.

Opioids such as morphine are frequently used for chronic pain management despite their many adverse effects. Ongoing research aims at either finding new treatments to replace opioids or reducing its heavy adverse effects due to long-term use: opioid-induced hyperalgesia and antinociceptive tolerance. In a recent study, Doyle et al. (2020) demonstrate that the activation of sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in a rodent model of chronic pain. By targeting S1PR1 with molecules with functional antagonistic properties (some of which are FDA-approved for multiple sclerosis treatment), hyperalgesia and tolerance were significantly reduced without modifying morphine pharmacokinetics or efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Morphine-induced alterations in sphingolipid metabolism in the spinal cord and increased formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) have been implicated in the development of morphine-induced hyperalgesia (OIH; increased pain sensitivity) and antinociceptive tolerance. These adverse effects hamper opioid use for treating chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5 G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to morphine remains unknown. Here, we report that S1P contributes to the development of morphine-induced hyperalgesia and tolerance through S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of morphine without altering morphine pharmacokinetics and prevented prolonged morphine-induced neuropathic pain. Targeting S1PR1 reduced morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression, mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory cytokine expression, such as interleukin-1β, a cytokine central in the modulation of opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate opioid-induced adverse effects and repurposing the functional S1PR1 antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct. [ABSTRACT FROM AUTHOR]

The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug. [Display omitted] • Compound 14 is a bifunctional agonist of mu opioid receptor and nociceptin-orphanin FQ opioid peptide receptor. • Compound 14 exhibits robust anticonception from the thermal nociceptive mouse model. • Compound 14 validated reduced side effects such as constipation, reward, tolerance and withdrawal effects. [ABSTRACT FROM AUTHOR]

Antinociceptive tolerance after repetitive administration of morphine severely limits its clinical use. Despite increased mechanistic understanding of morphine tolerance, little is known about the influence of dosing regimens in its development. We hypothesized that the starting dose of morphine, dosing frequency and dose increments, influence antinociception and the manifestation of antinociceptive tolerance in rats. Male rats were randomly divided into four groups with different intermittent starting-doses of daily morphine (b.i.d.) followed by different increments of single-dose morphine upon development of antinociceptive tolerance, for 2–3 weeks: 2.5 (b.i.d.)→5 → 10→15 mg/kg/day, 5 (b.i.d.)→10 mg/kg/day, 5 (b.i.d.)→15 mg/kg/day, 10 (b.i.d.)→20 mg/kg/day. Antinociception was assessed daily pre-treatment and at several time-points over 2 h post-administration, using tail-flick and hot-plate assays. Tolerance was defined as significant antinociceptive desensitization and was presented as significant reduction of the maximum and total antinociceptive efficacy upon morphine administration. Rats commenced on 2.5 mg/kg/day (b.i.d.) morphine developed tolerance faster than those started on 5 or 10 mg/kg/day (b.i.d.). Comparatively, higher starting and maintenance doses of morphine produced prolonged antinociception and delayed tolerance. Whereas, lower starting and maintenance doses of morphine produced less total antinociception during the course of treatment and did not delay the onset of tolerance, but require smaller dose-increments to reach antinociception after development of antinociceptive tolerance. These results suggest that morphine starting dose, dosing frequency, increments and timing determine the manifestation of antinociceptive tolerance and extent of antinociception. In addition, our results also highlight the need for generally standardized and validated assay protocols and procedures to compare different studies, as a prerequisite to translate pre-clinical results into the clinic. [ABSTRACT FROM AUTHOR]

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25 , and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED 50 value of 127.1 ± 34.65 μg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects. [Display omitted] • Benzo[b]thiophene-2-carboxamides were identified as potent opioid receptor agonists. • Compound 25 demonstrates potent antinociception in thermal nociceptive mouse model. • Compound 25 exerts less potent constipation than antinociception. • Compound 25 demonstrates less antinociceptive tolerance than morphine. [ABSTRACT FROM AUTHOR]

(−)-Morphine, but not (+)-morphine, interacts with μ-opioid receptors to produce antinociception (analgesia). The antinociception produced by (−)-morphine is attenuated by pretreatment with (+)-morphine or (−)-morphine given spinally, supraspinally, or systemically. This phenomenon has been defined as antianalgesia, which is induced by (+)-morphine or (−)-morphine against the (−)-morphine-induced antinociception following activation of the naloxone-sensitive σ receptors. In addition, (+)-morphine or (−)-morphine pretreatment attenuates the antinociception produced by δ-opioid receptor agonist deltorphin II or κ-opioid receptor agonist U50,488 H in μ-opioid receptor knockout mice. The antianalgesia induced by (+)-morphine or (−)-morphine against (−)-morphine-induced analgesia is mediated through activation of p38-mitogen-activated protein kinase. (−)-Morphine, but not (+)-morphine, induces the conditioned place preference, and the conditioned place preference induced by (−)-morphine is attenuated by pretreatment with (+)-morphine or (−)-morphine. Furthermore, (+)-morphine blocks the increase in the extracellular dopamine in the nucleus accumbens shell produced by μ-opioid agonist endomorphin-1 from the ventral tegmental area. These effects of (+)-morphine in attenuating the (−)-morphine-induced conditioned place preference and increased release of dopamine are also mediated through activating naloxone-sensitive σ receptors. In conclusion, the review article depicts the mechanisms involved in the acute antinociceptive (analgesic) tolerance to (−)-morphine and the attenuation of (−)-morphine-induced conditioned place preference (addiction) with (+)-morphine. [Copyright &y& Elsevier]

Abstract: The analgesic effectiveness of long-term opioid therapies is compromised by the development of antinociceptive tolerance linked to the overt production of peroxynitrite (ONOO−, PN), the product of the interaction between superoxide (O2 −, SO) and nitric oxide (NO), and to neuroinflammatory processes. We have recently reported that in addition to post-translational nitration and inactivation of mitochondrial manganese superoxide dismutase (MnSOD), activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase holoenzyme (NOX) in the spinal cord is a major source for the overt production of superoxide-derived PN during the development of morphine-induced antinociceptive tolerance. However, the NOX complex involved in these processes is not known. The objective of these studies is to identify a potential role for the NOX2 complex, an enzyme involved in inflammation. Mice lacking the catalytic subunit of NOX2 (Nox2 −/−) or its regulatory subunit, p47 phox (p47phox −/−), developed antinociceptive tolerance similar to wildtype (wt) mice after 3days of continuous morphine. However, while wt mice continue to develop tolerance by day six, morphine analgesia was restored in both Nox2 −/− and p47phox −/− mice. Moreover, the loss of Nox2 or p47 did not affect acute morphine analgesia in naïve mice. In wt mice, antinociceptive tolerance was associated with increased activation of NOX, nitration of MnSOD, and proinflammatory cytokines production in the spinal cord. These events were markedly attenuated in Nox2 −/− and p47phox −/− mice and instead, there was enhanced formation of antiinflammatory cytokine (IL4 and IL10) production. These results suggest that NOX2 activity provides a significant source of superoxide-derived PN to undertake post-translational modifications of mitochondrial MnSOD and to engage neuroinflammatory signaling in the spinal cord associated with opioid-induced antinociceptive tolerance. Thus, NOX2 may provide a potential target for adjuvant therapy to protect opioid analgesia. [Copyright &y& Elsevier]

Abstract: Repeated administration of opioids such as morphine leads to the development of tolerance to their pain-relieving effects as well as to physical dependence. Although the association between the dopamine system and the molecular mechanisms of morphine-induced antinociceptive tolerance has been studied, the possible interaction between morphine-induced tolerance and D3 receptors has not been investigated. In the present study, male mice lacking the dopamine D3 receptor gene were used to investigate the function of D3 receptors in the development of morphine-induced tolerance and withdrawal. Compared with wild-type (WT) mice, the dopamine D3 receptor knockout (D3R KO) mice showed pronounced hypoalgesia. The D3R KO mice clearly developed lower morphine-induced tolerance and showed attenuated withdrawal signs compared with the WT mice. These results suggest that D3 receptors regulate basal nociception and are involved in the development of morphine-induced tolerance and withdrawal. [Copyright &y& Elsevier]

Abstract: Aims: Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. Main methods: Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4mg/kg subcutaneously (s.c.) twice per day for 9days to male Sprague–Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [35S]GTPγS binding to the MOR and DOR. Key findings: Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [35S]GTPγS binding in the membranes of HEK293 cells expressing either the MOR or the DOR. Significance: LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR. [Copyright &y& Elsevier]

Abstract: The present study was designed to determine whether the p53 tumor-suppressor protein is involved in the development of antinociceptive tolerance to morphine. When the doses of morphine (mg/kg per injection) were subcutaneously given into mice as pretreatment twice daily for 2 days (first day (30) and second day (60)), intrathecal (i.t.) administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance in the 0.5% formalin test on the third day. Tolerance to i.t. morphine was significantly suppressed by i.t. injection of pifithrin-α (1 and 10nmol), an inhibitor of p53 activation, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) (1 and 10nmol), a non-selective caspase inhibitor, or N G-nitro-l-arginine methyl ester (l-NAME) (2 and 20nmol), a non-selective inhibitor of nitric oxide synthase, 5min before each morphine treatment during the induction, with none given on the test day. Moreover, p53 expression in the spinal cord had increased significantly 14h after the last morphine administration. These results indicate that the increased expression and activation of p53, and the nitric oxide and caspase systems related to p53 may contribute to the development of antinociceptive tolerance to morphine in the mouse spinal cord. [Copyright &y& Elsevier]

Abstract: The effects of various protease inhibitors on the development of antinociceptive tolerance to morphine were examined in mice. Intrathecal (i.t.) administration of morphine (0.01–1nmol) produced a dose-dependent and significant antinociceptive effect in the 0.5% formalin test. When the doses of morphine (mg/kg, s.c. per injection) were given as pretreatment twice daily for two days [first day (30) and second day (60)], i.t. administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance on the third day. Tolerance to i.t. morphine was significantly suppressed by the i.t. injection of N-ethylmaleimide or Boc-Tyr-Gly-NHO-Bz, inhibitors of cysteine proteases involved in dynorphin degradation, as well as by dynorphin A, dynorphin B and (−) U-50,488, a selective κ-opioid receptor agonist. On the other hand, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, lisinopril, an angiotensin-converting enzyme inhibitor, and phenylmethanesulfonyl fluoride, a serine protease inhibitor, were inactive. These results suggest that cysteine protease inhibitors suppress the development of morphine tolerance presumably through the inhibition of dynorphin degradation. [Copyright &y& Elsevier]

Abstract: Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (−)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction. [Copyright &y& Elsevier]

Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2 receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2 receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance. [ABSTRACT FROM AUTHOR]

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid–induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients. [Copyright &y& Elsevier]

Recent studies indicate that sustained opioid administration produces increased expression of spinal dynorphin, which promotes enhanced sensitivity to non-noxious and noxious stimuli. Such increased ‘pain’ may manifest behaviorally as a decrease in spinal antinociceptive potency. Here, the possibility of similar mechanisms in the antinociception of spinal cannabinoids was explored. Response thresholds to non-noxious mechanical and noxious thermal stimuli were assessed. Antinociception was determined using the 52°C tail-flick test. Mice received repeated WIN 55,212-2, its inactive enantiomer, WIN 55,212-3 or vehicle (i.th., bid, 5 days). WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced a time-related increased sensitivity to non-noxious and noxious stimuli. WIN 55,212-2, but not WIN 55,212-3 or vehicle, elicited a significant increase in lumbar spinal dynorphin content at treatment day 5. Increased sensitivity to mechanical and thermal stimuli produced by WIN 55,212-2 was reversed to baseline levels by i.th. MK-801 or dynorphin antiserum; control serum had no effect. WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced dose-related antinociception and repeated administration resulted in antinociceptive tolerance. While MK-801 and dynorphin antiserum did not alter acute antinociception produced by WIN 55,212-2, these substances significantly blocked antinociceptive tolerance when given immediately prior to WIN 55,212-2 challenge on day 5. Daily MK-801 pretreatments, prior to WIN 55,212-2 injection, also produced a significant block of antinociceptive tolerance. These data suggest that like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance. [Copyright &y& Elsevier]