Withdrawal responses of guinea-pig isolated ileum following brief exposure to opiates and opioid peptides

Summary Withdrawal contractures following brief exposure of guinea-pig ileum to enkephalin analogues, dynorphin A-(1-13) and beta-endorphin and the opiate drugs morphine, ketocyclazocine, buprenorphine and MR2034 were investigated. Following 2 min contact with the ileum a withdrawal contracture was induced by washout of (Met⁵)- and (Leu⁵)-enkephalin and by several enkephalin analogues but not by washout of (D-Ala²,D-Leu⁵)-enkephalinamide or any of the other drugs tested. Addition of naloxone precipitated withdrawal to all opioids tested except the kappa receptor preferential drugs ketocyclazocine and MR2034 and the mu receptor partial agonist, buprenorphine.The heights of the withdrawal contractures to enkephalin analogues were found to be dependent on the concentration of agonist and of naloxone, and on the duration of the contact period of opioid with the ileum.The naloxone-precipitated withdrawal responses to morphine, dynorphin A-(1-13) and the washout withdrawal response to (Met⁵)-enkephalin were inhibited by substance P antagonists thus supporting the previous pro posal that substance P mediates the opiate withdrawal response.This study has shown that mu receptor agonists produced dependence in the guinea-pig ileum revealed by a withdrawal contracture on addition of naloxone, whereas dependence on kappa receptor agonists could not be revealed with naloxone. Since the guinea-pig ileum preparation has m and kappa receptors it was concluded that the endogenous opioid peptides, enkephalins, beta-endorphin and dynorphin A-(1-13), all induced dependence by acting on mu receptors in this preparation.     

[3H]5′-N-ethylcarboxamide adenosine binds to both Ra and Ri adenosine receptors in rat striatum

Summary Adenosine analogs such as 5-N-ethylcarboxamide adenosine and N⁶-cyclohexyladenosine stimulate or inhibit adenosine cyclase activity in preparations of rat striatum depending on the assay conditions. N⁶-cyclohexyladenosine inhibits but does not stimulate adenosine cyclase activity in preparations of hippocampus. These findings suggest that the striatum contains both R _a (stimulatory) and R _i (inhibitory) adenosine receptors while the hippocampus contains only R _i receptors. We have previously shown that [³H]N⁶-cyclohexyladenosine binds to R _i receptors in rat hippocampus (Yeung and Green 1983). Comparisons of the characteristics of [³H]5-N-ethylcarboxamide adenosine and [³H]N⁶-cyclohexyladenosine binding to hippocampus show that [³H]5-N-ethylcarboxamide adenosine also binds to R _i receptors with high affinity. [³H]5-N-ethylcarboxamide adenosine binds to R _i receptors in the striatum and to a second site that is present in striatum but not hippocampus. High affinity binding of both ligands to R _i receptors can be blocked by treatments with N-ethylmaleimide that do not markedly affect [³H]5-N-ethylcarboxamide adenosine binding to the second site in the striatum. The pharmacological characteristics of the second site indicate that it is the R _a adenosine receptor.The abbreviations used are NEM N-ethylmaleimide - Gpp(NH)p 5-guanylylimidodiphosphate - NECA 5-N-ethylcarboxamide adenosine - l-PIA N⁶-(l-phenylisopropyl)adenosine - d-PIA N⁶-(d-phenylisopropyl) adenosine - DPX 1,3-diethyl-8-phenylxanthine     

Clonidine dependence in the guinea-pig isolated ileum

1 Compared with the response of preparations incubated in solutions without clonidine, a three to four fold increase in the magnitude of the contracture of the longitudinal muscle to challenge with phentolamine (1.0 μm) was induced by incubating the guinea-pig isolated ileum at 22°C for 24 h with clonidine (1.0 μm) in Krebs solution containing hexamethonium (70 μm). Incubation of the ileum with clondine (1.0 μm) for 0.5 h at 37°C did not increase responsiveness to phentolamine.2 The increase in responsiveness to phentolamine was directly related to the clonidine concentration in the incubation fluid over the range 0.01 to 1.0 μm.3 The magnitude of the contracture to phentolamine of ilea incubated with clonidine (1.0 μm) (withdrawal contracture) was directly related to the challenge dose of phentolamine over the range 0.3 to 1.0 μm.4 Yohimbine (1.0 μm) or piperoxane (1.0 μm) elicited a response comparable to that elicited by phentolamine but propranolol (1.0 μm) was inactive.5 Addition of phentolamine (1.0 μm) to clonidine (1.0 μm) in the incubation fluid abolished the increased response of the preparation to subsequent challenge with phentolamine.6 Addition of hyoscine (0.5 μm) immediately after challenge with phentolamine restored the tension of the withdrawal contracture to its resting level.7 Tetrodotoxin (3.0 μm) given before challenge, prevented phentolamine from eliciting a withdrawal contracture.8 Ileal segments incubated with clonidine (1.0 μm) were unresponsive to challenge with naloxone (100 nm); and segments incubated with normorphine (1.0 μm) were unresponsive to phentolamine (1.0 μm), although responsive to naloxone.9 Normorphine (1.0 μm) restored to resting level the tension of the clonidine withdrawal contracture; and clonidine (0.1 μm) restored to resting level the tension of the contracture to naloxone in ileal segments incubated with normorphine.10 These experiments indicate that incubation with clonidine induces, in the final cholinergic motor neurones of the myenteric plexus of the isolated ileum, a dependence the withdrawal from which is expressed as a contracture in response to α-adrenoceptor antagonists.11 Although opiate receptors are not involved in clonidine dependence nor α-adrenoceptors in opiate dependence, the findings that normorphine suppresses the clonidine withdrawal-contracture and that clonidine suppresses the contracture of opiate-dependent ileum to naloxone, suggest that the withdrawal effect studied in both clonidine and normorphine dependence in this preparation is mediated by release of acetylcholine from the final motor neurone.     

Opioid dependence in the guinea-pig myenteric plexus is controlled by non-tolerant and tolerant opioid receptors

The experiments concerned the association of opioid dependence with specific opioid receptors. Previous investigations have demonstrated that tolerance may be confined to only one type of opioid receptor. These findings could suggest that dependence develops invariably only with receptors which have been rendered tolerant. We report here that in the guinea-pig isolated ileum, which has been made selectively tolerant to a μ-receptor agonist, naloxone may precipitate a sign of dependence at μ-receptors chronically activated and at naive κ-receptors. Furthermore, suppression of the withdrawal contracture in preparations rendered dependent on a μ-receptor agonist can be achieved by very low concentrations of a κ-agonist, e.g. dynorphin A. These findings challenge the current concept that confines drug dependence only to that opioid receptor type which has been activated chronically.     

Acute withdrawal induced by adenosine A1‐receptor activation in isolated guinea‐pig ileum: role of opioid receptors and effect of cholecystokinin

Objectives In isolated guinea‐pig ileum, the μ‐opioid acute withdrawal response is under control of several neuronal systems, including the κ‐opioid and the A₁‐adenosine systems, which are involved in the μ‐withdrawal response inhibitory control. After μ‐opioid system stimulation, indirect activation of both κ‐opioid and A₁‐adenosine systems is prevented by the peptide cholecystokinin‐8 (CCk‐8). Guinea‐pig ileum exposed to A₁‐adenosine agonist (CPA), shows a withdrawal contracture precipitated by the A₁‐adenosine antagonist (CPT). We investigated this response. Methods We investigated the involvement of the opioid system in the A₁‐adenosine acute withdrawal response in guinea‐pig ileum, the potential induced cross‐dependence between the A₁ and the opioid system and also the interaction between the CCk‐8 and A₁ systems. Key findings We found that in the guinea‐pig ileum preparation exposed to CPA, μ‐ and κ‐opioid antagonists increased the withdrawal response to CPT. Tissues exposed to CPA showed a contractile response to the opioid receptor antagonist naloxone only after complete removal of the A₁‐agonist. In the presence of CPA, the response to CCk‐8 was inhibited while a significant increase in CPT response intensity was observed. Conclusions In guinea‐pig ileum, stimulation of the A₁ system indirectly activates both μ‐ and κ‐opioid systems; this indirect activation is significantly, albeit not completely, antagonised by CCk‐8. Cross dependence between A₁ and opioid systems was also observed.     

Opioid dependence and cross-dependence in the isolated guinea-pig ileum

The development of opioid dependence and tolerance attributed to selective types of opiate receptors was studied in the isolated ileum of guinea pigs chronically exposed to specific opioids. These investigations were based on reports that in this preparation highly tolerant opiate receptors may coexist with opiate receptors of almost unchanged sensitivity. Thus, the ilea were set up in vitro and tested for tolerance and dependence. Apparently precipitation of the withdrawal contracture, indicating dependence, proved a more sensitive parameter than the phenomenon of tolerance. Maximal dependence was determined at rather low degrees of tolerance (5 to 10 fold). The intensity of the withdrawal contracture failed to increase as opiate tolerance did. Furthermore, the experiments failed to present evidence for the existence of selective dependence at specific opiate receptor types. These findings may suggest multiple adaptational mechanisms upon chronic activation of opiate receptors. One mechanism may be responsible for the development of dependence and a low degree of tolerance, whilst a further increase of tolerance may be associated with changes at the opiate binding site level.     

Differential influence of D1 and D2 dopamine receptors on acute opiate withdrawal in guinea-pig isolated ileum

1. The effects exerted by D₁ and D₂ dopamine agonists and antagonists on the acute opiate withdrawal induced by μ- and κ-receptor agonists were investigated in vitro.
2. Following a 4 min in vitro exposure to morphine (moderately selective μ-agonist), [D-Ala², Me-Phe⁴, Gly-ol⁵]enkephalin (DAMGO, highly selective μ-agonist) or U-50488H (highly selective κ-agonist) the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone.
3. The non-selective dopamine receptor antagonist haloperidol when added before or after the opioid agonists, was able dose-dependently to prevent or to reverse the naloxone-induced contracture after exposure to μ- (morphine and DAMGO) and κ- (U-50488H) opioid agonists. The non-selective dopamine receptor agonist, apomorphine, was able to exert the same effects only at the highest concentration used.
4. The selective D₂ dopamine receptor antagonist, sulpiride, was also able to reduce dose-dependently both μ- and κ-opioid withdrawal, whereas the D₁-receptor selective antagonist SCH 23390 did not affect either μ- or κ-opioid withdrawal.
5. Bromocriptine, a D₂ selective dopamine receptor agonist was able to increase significantly, and in a concentration-dependent manner, the naloxone-induced contracture by μ- and κ-opioid agonists, whereas SKF 38393, a D₁ selective dopamine receptor agonist, increased only the withdrawal after morphine or U50-488H.
6. Our data indicate that both D₁ and D₂ dopamine agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the dopaminergic system and opioid withdrawal at both the μ- and κ-receptor level.
7. Furthermore, the ability of sulpiride to block strongly opiate withdrawal when compared to SCH 23390, as well as the effect of bromocriptine to increase opiate withdrawal suggest that D₂ dopamine receptors may be primarily involved in the control of opiate withdrawal.

     

Outcomes from the International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) project

Aims: The International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) study evaluated the implementation of opioid dependence treatment across different countries to assess treatment delivery, quality of care and outcomes. Methods: A questionnaire-based survey was used to gather data in nine countries across Central and Eastern Europe, South Africa and South-East Asia, from patients with opioid dependence receiving medication-assisted treatment (MAT), healthcare professionals (HCPs) who cared for opioid-dependent patients and opioid users not receiving MAT. Findings: There was substantial variation between countries, but overall results suggest that several aspects of MAT can be improved, such as access to treatment (conditions to start or remain in treatment), quality of care (availability/awareness of treatment options and appropriate medication dosing) and treatment outcomes (on-top use, misuse and diversion). Conclusions: This analysis highlights key priorities that should improve the quality of opioid dependence care and access to treatment. These priorities include: acknowledging opioid dependence as a chronic medical condition requiring long-term treatment; recognition by policymakers of the cost-effectiveness of treatment; making available, to those who want them, psychosocial interventions and educating HCPs to prescribe the safest, least divertible forms of medications available at optimal doses in order to reduce opioid use, misuse and diversion.     

A Systematic Approach to Drug Abuse Treatment Referral

Abstract

The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and AlcoholMD.com.     

Inhibition of pacemaker current by the bradycardic agent ZD 7288 is lost use-dependently in sheep cardiac Purkinje fibres

The inhibition of the pacemaker current (i _f) in sheep cardiac Purkinje fibres by ZD 7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride] is lost use-dependently. This disinhibition of i _f was investigated by using the two-microelectrode voltage-clamp technique. The pulse protocol consisted of a rest period (holding potential of about -50 mV, 1–10 mol/l ZD 7288) followed by a train of test pulses (potential negative to -100 mV, stimulation frequency 0.05 Hz). At the beginning of the first test pulse there was an immediate reduction of i _f but inhibition was lost during continued stimulation. Activation of i _f is sigmoidal and the early delay in current activation was prolonged from 33 ms (no ZD 7288) to 424 ms (10 mol/l ZD 7288). Therefore hardly any disinhibition occurred during short test pulses (0.5 s). During longer test pulses (5 s, -120 mV, 10 mol/l) disinhibition developed with a time constant of about 2 s. The inhibition of i _f by ZD 7288 was lost voltage-dependently. With 10 mol/l ZD 7288 the half-maximal disinhibition occurred at -92 mV and the slope factor of the disinhibition/voltage curve (Boltzmann relation) was 4.8 mV. The voltage-dependent disinhibition could be abolished largely by extracellular application of protease (0.5 mg/ml, 7 min). After prior disinhibition, reinhibition at the holding potential (about -50 mV) followed a bi-exponential time course indicating that inhibition may be produced by a fast (=0.7 min) and a slow component (=20–30 min). Increasing ZD 7288 concentration from 1 to 10 mol/l accelerated reinhibition, mainly by an increase of the amplitude (A) of the fast component. The ratio A _fast/A _sIow was 0.399 at 1 mol/l and 2.65 at 10 mol/1 ZD 7288. The reinhibition of i _f was unchanged by shifting the holding potential from -50 mV to -20 mV Trials to wash out the effects of 10 mol/l ZD 7288 gave two results. The inhibition of i _f was slightly reversed after a wash-out of 1.5 h with drug-free solution. A second effect of the drug, the fast reinhibition, could be completely removed by washout. In summary i _f is inhibited by ZD 7288 at membrane potentials at which the virtual i _f gate is closed. Disinhibition occurs during long-lasting hyperpolarization but will hardly be operative in unclamped fibres under physiological conditions.     

Possible role of cyclic AMP in the relaxation process of mammalian heart: Effects of dibutyryl cyclic AMP and theophylline on potassium contractures in cat papillary muscles

Summary The effect of dibutyryl cyclic AMP (DB-c-AMP; 3×10^–4–3×10^–3 M) on electrically induced twitch and high potassium (142.4 mM KCl)-induced contracture tension was studied in papillary muscles from normal and reserpinized cats ([Ca]₀ 1.8 mM; 25°C; pH 7.4). In both groups of preparations, the increase in twitch tension evoked by DB-c-AMP was accompanied by an abbreviation of the time to peak force and of relaxation time. In the same preparations, the high potassium contracture was markedly depressed by DB-c-AMP in a concentration-dependent manner. Similar results were obtained with the N⁶-monobutyryl derivative of cyclic AMP.The relaxing effects of the cyclic nucleotides on KCl contractures did not appear to be due to possible non-cyclic breakdown products: adenosine; 5-AMP and sodium butyrate did not attenuate contracture tension at concentrations up to 3×10^–3 M. The same applies to ATP and non-cyclic N⁶-2-O-3-O-tributyryl-adenosine-monophosphate. Theophylline (10^–2 M) was found to prolong the relaxation time of the twitch and to enhance the high KCl contracture.It is concluded that cyclic AMP may be capable of modulating the relaxation process of mammalian heart and that not only the positive inotropic but also the relaxant effects of catecholamines on myocardium described before may be mediated by the cyclic AMP system. The relaxant effects of cyclic AMP derivatives on intact myocardial preparations are attributed to a stimulation by cyclic AMP of the calcium transport of the sarcoplasmic reticulum (SR) and are interpreted to be a corollary to the effects of cyclic AMP previously obtained on isolated SR preparations.     

Pharmacological mechanisms underlying the antinociceptive and tolerance effects of the 6,14-bridged oripavine compound 030418

Aim:

To investigate possible pharmacological mechanisms underlying the antinociceptive effect of and tolerance to N-methyl-7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydronororipavine (030418), a derivative of thienorphine.

Methods:

The binding affinity and efficacy of 030418 were determined using receptor binding and guanosine 5′-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) assays in CHO-μ, CHO-κ, CHO-δ, and CHO-ORL1 cell membranes. The analgesic activity of and tolerance to 030418 were evaluated in thermal nociceptive tests in mice. The effects of 030418 on opioid receptors were further investigated using in vivo pharmacological antagonist blockade and in vitro tissue preparations.

Results:

The compound 030418 displayed high binding affinity to all subtypes of opioid receptors with K_i values in the nanomolar range. In [³⁵S]GTPγS binding assay, the maximal stimulation of 030418 to μ-, κ-, δ-receptors and the ORL1 receptor was 89%, 86%, 67% and 91%, respectively. In hot-plate test, the antinociceptive effect of 030418 was more potent and longer than morphine. The nonselective opioid receptor antagonist naloxone could completely block 030418-induced antinociception, while both the μ-opioid receptor antagonist β-FNA and the κ-opioid receptor antagonist nor-BNI attenuated 030418-induced antinociception. In contrast, the ORL1 receptor antagonist J-113397 enhanced the antinociceptive effect of 030418. Additionally, chronic treatment with 030418 resulted in a dramatic development of tolerance that could not be effectively prevented by J-113397. In guinea pig ileum preparation, the existing action of 030418 could be removed with difficulty after prolonged washing.

Conclusion:

The compound 030418 is a novel agonist of opioid receptors with high efficiency, long-lasting effect and liability to tolerance, which may be closely correlated with the methyl group at the N₁₇ position and the high hydrophobicity of the C₇-thiophene group in its chemical structure.     

Attenuation of morphine withdrawal symptoms by subtype-selective metabotropic glutamate receptor antagonists

1. We have previously shown that chronic antagonism of group I metabotropic glutamate receptors (mGluRs), in the brain, attenuates the precipitated morphine withdrawal syndrome in rats. In the present investigation we assessed the effects of chronic antagonism of group II and III mGluRs on the severity of withdrawal symptoms in rats treated chronically with subcutaneous (s.c.) morphine.
2. Concurrently with s.c. morphine we infused intracerebroventricularly (i.c.v.) one of a series of phenylglycine derivatives selective for specific mGluR subtypes. Group II mGluRs (mGluR_2,3), which are negatively coupled to adenosine 3′: 5′-cyclic monophosphate (cyclic AMP) production, were selectively antagonized with 2s, 1′s, 2′s-2-methyl-2-(2′-carboxycyclopropyl) glycine (MCCG). Group III mGluRs (mGluR_{4,6,7 and 8}), which are also negatively linked to cyclic AMP production, were selectively antagonized with α-methyl-L-amino-4-phosphonobutanoate (MAP4). The effects of MCCG and MAP4 were compared with α-methyl-4-carboxyphenylglycine (MCPG), which non-selectively antagonizes group II mGluRs, as well as group I mGluRs (mGluR_1,5) which are positively coupled to phosphatidylinositol (PI) hydrolysis.
3. Chronic i.c.v. administration of both MCCG and MAP4 significantly decreased the time spent in withdrawal, MCPG and MCCG reduced the frequency of jumps and wet dog shakes and attenuated the severity of agitation.
4. Acute i.c.v. injection of mGluR antagonists just before the precipitation of withdrawal failed to decrease the severity of abstinence symptoms. Rather, acute i.c.v. injection of MCCG significantly increased the time spent in withdrawal.
5. Our results suggest that the development of opioid dependence is affected by mGluR-mediated PI hydrolysis and mGluR-regulated cyclic AMP production.

     

Demonstration of Ri-type adenosine receptors in bovine myocardium by radioligand binding

Summary Adenosine has been shown to have negative inotropic, chronotropic and dromotropic effects on the heart. The pharmacological profiles of these effects suggest that they are mediated via R_i (A₁) adenosine receptors, but a direct demonstration of these receptors is still missing. In the present study we report direct labelling of these receptors with (-)N⁶-[¹²⁵I]-p-hydroxyphenylisopropyladenosine ([¹²⁵I]HPIA). The radioligand bound in a saturable and reversible manner to a crude membrane preparation, the B _max-value was 30.5 fmol/mg protein and the K _D-value 1.1 nmol/l. A similar affinity of the ligand was obtained in kinetic and competition experiments. Competition experiments with a variety of adenosine analogues gave a pharmacological profile characteristic of R_i adenosine receptors with high affinities of N⁶-substituted derivatives and a marked stereospecificity for N⁶-phenylisopropyladenosine (PIA). Purification of the membrane preparation by density gradient centrifugation resulted in a 30-fold increase in the number of binding sites which was paralleled by a similar increase in the number of binding sites for [³H]ouabain. Guanine nucleotides decreased binding of [¹²⁵I]HPIA in a dose-dependent manner, but the IC₅₀-values were considerably higher than those reported in other tissues. Finally, binding of [¹²⁵I]HPIA appeared to be entropy-driven which has been shown to be characteristic of agonist binding to R_i adenosine receptors. These results suggest the presence of R_i adenosine receptors in ventricular myocardium which may be responsible for the mediation of the effects of adenosine and its analogues.Abbreviations [¹²⁵I]HPIA (-)N⁶-[¹²⁵I]-p-hydroxyphenylisopropyladenosine - (-)IHPIA (-)N⁶-iodo-p-hydroxyphenylisopropyladenosine - (+)/(-)PIA (+)/(-)N⁶-phenylisopropyladenosine - CHA N⁶-cyclohexyladenosine - NECA 5-N-ethylcarboxamidoadenosine - App(NH)p 5-adenylylimidodiphosphate - Gpp(NH)p 5-guanylylimidodiphosphate     

The role of adenosine A1 receptors in the nucleus accumbens during morphine withdrawal

Opioids are effective analgaesic agents, but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is not life-threatening. Studies have shown that the mesocorticolimbic system, especially the nucleus accumbens, is an important region in drug addiction and adenosine receptors play a modulatory role in the mechanism of action of drug dependence and withdrawal. The aim of this study was to investigate the effects of the selective A₁ receptor agonist CPA (N⁶-cyclopentyladenosine) on withdrawal symptoms, and the concentration of dopamine and noradrenaline in the nucleus accumbens and locomotor activity behaviour during naloxone-precipitated withdrawal in morphine-dependent rats. The local administration of CPA (1.5, 3.0, and 6.0 mmol/L bilateral 250 nL) into the nucleus accumbens decreased the Gellert–Holtzman withdrawal scale, and increased concentrations of dopamine and noradrenaline in the same region during naloxone-induced withdrawal. Our findings suggest that administration of the A₁ receptor agonist significantly decreased withdrawal behaviours and increased dopamine and noradrenaline concentrations in opioid withdrawal in a dose-dependent manner. These results demonstrate that adenosine receptors should be examined as a potential mechanism that could be exploited for the treatment of morphine withdrawal.     

Buprenorphine and buprenorphine/naloxone soluble-film for treatment of opioid dependence

Introduction: Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information.

Expert opinion: This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits.     

TH-030418: a potent long-acting opioid analgesic with low dependence liability

Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to μ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K _i values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED₅₀ values of 1.37 μg/kg and 1.70 μg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.     

A Stage I pilot study of acceptance and commitment therapy for methadone detoxification

Background

While agonist replacement therapies are effective for managing opioid dependence, community treatment programs are increasingly choosing detoxification. Unfortunately, success rates for opioid detoxification are very low, in part, due to physical and psychological symptoms associated with opioid withdrawal. Few behavior therapies specifically address the distressing experiences specific to opioid withdrawal. A novel behavioral treatment, acceptance and commitment therapy (ACT), works from the premise that the avoidance of unpleasant private experiences (thoughts, feelings, bodily sensations) is ubiquitous yet may be pathogenic, resulting in treatment drop-out and further drug use.

Methods

This Stage I pilot study developed and tested an ACT-based opioid detoxification behavioral therapy. Opioid dependent patients (N = 56) who were attending a licensed methadone clinic were randomized to receive either 24 individual therapy sessions of ACT or drug counseling (DC) in the context of a 6-month methadone dose reduction program.

Results

While no difference was found on opioid use during treatment, 37% of participants in the ACT condition were successfully detoxified at the end of treatment compared to 19% of those who received DC. Fear of detoxification was also reduced across time in the ACT condition relative to DC.

Conclusion

This first study of ACT to assist opioid detoxification indicates promise. Research is needed to refine specific treatment strategies for this population to further strengthen effects.     

The influence of chronic treatment with clonidine, yohimbine and idazoxan on morphine withdrawal

Numerous previous attempts have been made to study the involvement of α₂-adrenoceptors in the expression of morphine withdrawal by studying the effects of selective α₂-agonists and antagonists administered immediately before precipitation of withdrawal by an opioid antagonist such as naloxone. In the present investigation, we examined the effects of chronic treatment with clonidine (α₂-agonist), idazoxan and yohimbine (α₂-antagonists), concomitantly administered with morphine, on the expression of the withdrawal signs. In contrast to their acute effects, clonidine potentiated, while yohimbine and idazoxan attenuated the withdrawal signs precipitated by naloxone in morphine-dependent mice. In addition, mice chronically treated only with yohimbine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were not influenced by naloxone administration. Mice chronically treated with clonidine displayed withdrawal signs similar to those reported with morphine withdrawal and these signs were further potentiated by naloxone administration. The results suggest that down-regulation of α₂-adrenoceptors by morphine is a major adaptation contributing to development of dependence on opioids and also point the way to more effective treatment of narcotic dependence. This suggestion was based on the hypothesis that the suppression of noradrenergic system during chronic morphine treatment by α₂-antagonists might diminish noradrenergic hyperactivity and consequently the development of dependence and withdrawal signs. Received: 5 October 1996/Final version: 28 January 1997     

Cyclic nucleotide phosphodiesterases of human and rat gastric mucosa

Summary Cyclic adenosine-3,5-monophosphate (cAMP) phosphodiesterases (PDE) were partially purified from human and rat gastric mucosa. Drugs known to affect the cyclic nucleotide system and/or gastric secretion were tested for effects on the PDE-activities from both species.In rat gastric mucosa PDE-activity can be detected in the 100 000×g sediment (K _m =8.3 M; V _max=3.2 nmoles cAMP hydrolyzed/mg protein x min) and the cytoplasma (K _m =5.6 M; V _max=2.6 nmoles cAMP hydrolyzed/mg protein x min).The most effective inhibitors of the particle-bound activity are papaverine (K _i =4 M, non-competitive) and 3-isobutyl-1-methylxanthine (K _i=14 M, competitive). There was only a modest competitive inhibition by theophylline (K _i =495 M). PDE-activity in the cytoplasma was inhibited competitively by these three drugs (papaverine: K _i =6.5 M; 3-isobutyl-1-methylxanthine: K _i =37 M; theophylline: K _i =152 M.In human gastric mucosa PDE-activity can be detected in the particular fraction (K _m =23.9 M; V _max=1.2 nmoles cAMP hydrolyzed/mg protein x min), and the soluble fraction (K _m =12.1 M; V _max=2.4 nmoles cAMP hydrolyzed/mg protein x min).PDE-activity in the 100 000×g sediment was inhibited by papaverine (K _i =5.6 M, non-competitive), 3-isobutyl-1-methylxanthine (K _i =16 M, non-competitive), theophylline (K _i =165 M, non-competitive), and N₆-2-O-dibutyryl-cAMP (K _i =746 M, competitive).Inhibition in the 100 000×g supernatant was noncompetitive with 3-isobutyl-1-methylxanthine (K _i =7.1 M and papaverine (K _i =8.5 M), but competitive with N₆-2-O-dibutyryl-cAMP (K _i =170 M), and theophylline (K _i =225 M). This study indicates that PDE-activities of the two species are qualitatively similar, but quantitative differences exist.