The dopamine D3/2 agonist 7-OH-DPAT attenuates the development of morphine tolerance but not physical dependence in rats

RATIONALE: The dopamine (DA) D3/2 agonist 7-OH-DPAT attenuates the acute antinociceptive, discriminative stimulus, locomotor activating, and reinforcing effects of mu agonists (for example, morphine). OBJECTIVES: To examine the ability of 7-OH-DPAT to modulate the development of morphine tolerance and physical dependence in the rat. METHODS: Morphine antinociception was assessed using a warm water tail-withdrawal procedure before and following chronic treatment with morphine (15 mg/kg)/7-OH-DPAT (0.3-3.0 mg/kg). Physical dependence was assessed following naloxone-precipitated (1.0 mg/kg) withdrawal in rats treated chronically with morphine (15 and 7.5 mg/kg)/7-OH-DPAT (1.0-10 mg/kg). RESULTS: 7-OH-DPAT attenuated the antinociceptive effects of morphine in both morphine naive and tolerant rats. Additionally, morphine tolerance was attenuated by the coadministration of 7-OH-DPAT in a dose- and time-dependent manner. The magnitude of the attenuation obtained when morphine and 7-OH-DPAT were administered at the same time was similar to that obtained when administration of these drugs was separated by 6 h, indicating that 7-OH-DPAT did not alter morphine pharmacokinetics. In rats rendered tolerant to morphine, the subsequent coadministration of morphine/7-OH-DPAT failed to reverse morphine tolerance, but did attenuate its further development. The level of physical dependence (number and frequency of withdrawal signs) was greater in rats treated with 15 than 7.5 mg/kg morphine. Under both treatment conditions, physical dependence was not altered by 7-OH-DPAT. In morphine-dependent (15 mg/kg) rats, 7-OH-DPAT (3.0 and 10 mg/kg) failed to precipitate withdrawal. CONCLUSION: The D3/2 agonist 7-OH-DPAT can attenuate the antinociceptive effects of morphine in both acute and chronic preparations as well as the development of morphine tolerance. 7-OH-DPAT does not, however, alter morphine physical dependence.     

Role of morphine maintenance dose in the development of tolerance and its attenuation by an NMDA receptor antagonist

Rationale: Current research shows that N-methyl-d-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance in rodent antinociceptive assays. Objective: The purpose of this study was to determine the role of morphine maintenance dose in the attenuation of morphine tolerance by the competitive NMDA receptor antagonist, LY235959. Methods: A rat warm-water tail-withdrawal procedure was used to measure the antinociceptive effects of morphine and LY235959. In this procedure, the distal 8 cm of each rat’s tail is immersed in 40° (non-noxious) and 55°C (noxious) water, and the latency to remove the tail is recorded. Results: Morphine (0.3–10 mg/kg, SC) produced dose-dependent increases in tail-withdrawal latencies from the 55°C water. Following determination of the morphine dose-effect curves, rats were administered chronically one of three doses of morphine (10, 20, or 40 mg/kg) either alone or in combination with LY235959 (1.0, 3.0, or 5.6 mg/kg, SC) twice daily for 7 days. Chronic administration of 10, 20, and 40 mg/kg morphine produced rightward shifts in the morphine dose-effect curves of approximately 3-, 6-, and 12-fold, respectively. When LY235959 (1.0–5.6 mg/kg) was co-administered with 10 mg/kg morphine, the development of morphine tolerance was attenuated in a dose-dependent manner, with complete prevention observed following 3.0 mg/kg LY235959. LY235959 (1.0, 3.0 mg/kg) also attenuated the development of tolerance to 20 and 40 mg/kg morphine; however, tolerance was not completely prevented. Administering 3.0 mg/kg LY235959 along with 20 and 40 mg/kg morphine was functionally equivalent to treating rats with half the amount of morphine. Conclusion: These data suggest that the maintenance dose of morphine, and thus the magnitude of tolerance, can determine the effectiveness of an NMDA receptor antagonist to attenuate morphine tolerance. Received: 5 April 1999 / Final version: 23 July 1999     

Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats

 The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED₅₀ for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED₅₀ for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED₅₀ for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED₅₀ for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist. Received: 17 September 1996 / Final version: 13 March 1997     

Effects of the analgesic agent tramadol in normal and arthritic rats: comparison with the effects of different opioids, including tolerance and cross-tolerance to morphine

The effects of the analgesic agent tramadol (0.1-1 mg/kg i.v.) were compared to those of the mixed agonist-antagonist analgesics nalbuphine (1 mg/kg i.v.) and buprenorphine (3 micrograms/kg i.v.) in the vocalization threshold to paw pressure test. Normal and Freund's adjuvant-induced arthritic rats were used. We have shown previously that these animals used as a model of clinical pain exhibit an enhanced sensitivity to morphine (0.1-1 mg/kg i.v.), with a rapid development of tolerance after repetitive low doses, a response not observed in normal rats. In the present study, the antinociceptive effects of tramadol, buprenorphine and nalbuphine were enhanced (by 2- to 5-fold) in arthritic compared to normal rats. In this model, these effects were significantly reduced by a dose of naloxone (0.1 mg/kg i.v.) that completely antagonized the effect of morphine. In this model, the antinociceptive effect of tramadol (1 mg/kg i.v.) was comparable to that of nalbuphine (1 mg/kg i.v.), buprenorphine (3 micrograms/kg i.v.) and morphine (1 mg/kg i.v.). Repeated administration of low doses of tramadol twice daily for 4 days to arthritic rats did not induce tolerance, in contrast to nalbuphine, buprenorphine, and morphine. In addition, no cross-tolerance between tramadol and morphine was observed in these animals.     

The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence

U-50,488, a selective κ-opioid receptor agonist, has been reported to inhibit the development of antinociceptive tolerance to morphine in mice, rats and guinea pigs, but the mechanism involved in this action remains unknown. Since U-50,488 has been reported to supress the plasma vasopressin level, we investigated the role of vasopressin with U-50,488 in the male Sprague Dawley rat in this study. Animals (230–270 g) were chronically treated with morphine (10 mg/kg, i.p.) twice a day for 6 days in order to induce tolerance to antinociceptive effect measured by tail-flick test. Withdrawl symptoms were precipitated by naloxone (10 mg/kg, i.p.) on day 7. U-50,488 (i.p.) or AVP (i.p. or i.c.v.) or U-50,488 and AVP was (were) coadministered with chronic morphine to investigate their effects on morphine tolerance and dependence. We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms. In contrast, coadministration of AVP (0.3 μg/kg, i.p., or 0.01 μg, i.c.v.) with morphine and U-50,488, the effects of U-50,488 to block morphine tolerance and dependence were reversed. In addition, treatment of AVP antagonist (dPTyr(Me)AVP, 0.5 μg/kg, i.p. or 0.5 μg, i.c.v.) has the similar effect as U-50,488 to block morphine tolerance. In summary, the effect of U-50,488 to block morphine tolerance and dependence may relate to its inhibitory effect on AVP release. Received: 20 February 1996 / Accepted: 14 October 1996     

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor

  Rationale: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. Objective: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. Methods: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50°C (low temperature) and 55°C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (–)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. Results: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (–)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (–)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. Conclusions: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone. Received: 27 June 1998 / Final version: 7 November 1998     

Effects of atrial natriuretic peptide on acute and chronic effects of morphine.

Atrial natriuretic peptide (ANP) is known to participate in different vegetative functions. The aim of the present study was to investigate the influence of ANP on nociception itself, pain sensitivity to morphine, and the development of acute and chronic tolerance to morphine. Morphine withdrawal signs were also evaluated by injecting naloxone. In adult, male NMRI mice, ANP administered SC or ICV did not affect pain sensitivity itself in a heat-radiant tail-flick test. Peptide treatment, however, depressed the acute nociceptive effect of a single dose of morphine (4 mg/kg, SC) after both SC (20-200 ng/animal) and ICV (5, 10, 20, or 200 ng/animal) ANP administration. ANP given SC and ICV attenuated the development of acute morphine tolerance. Acute morphine tolerance was assessed by giving a bolus injection of morphine (60 mg/kg) 24 h before the pain sensitivity to a challenge dose of morphine (4 mg/kg) was measured. ICV treatment with ANP also blocked the development of chronic morphine tolerance, but did not affect the appearance of naloxone-precipitated withdrawal syndromes. ANP seems to act differently on the development of tolerance to and dependence upon morphine.     

The morphine sparing effect of physostigmine

The antinociceptive effect of morphine was studied in tail-flick- and acetic acid-induced writhing in mice. Morphine effect was dose-related (1, 2 and 5 mg/kg s.c.). Physostigmine (0.05 and 0.1 mg/kg i.p.) potentiated the antinociceptive effect of morphine, and the anticholinergic, scopolamine (1 mg/kg i.p.), reversed the potentiating effect of physostigmine, indicating the involvement of the cholinergic system in pain. Coadministration of physostigmine would increase the therapeutic index of morphine thereby sparing the dose of morphine and also possibly the side effects including the development of tolerance and addiction.     

Inhibitory effects of MPEP,an mGluR5 antagonist,and memantine,an <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate receptor antagonist,on morphine antinociceptive tolerance in mice

Abstract Rationale. Inhibition of N-methyl-D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. Objective. In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. Methods. Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose–response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. Results. MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. Conclusions. The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance. Electronic Publication     

Changes in sensitivity to the rate-decreasing effects of opioids in pigeons treated acutely or chronically with nalbuphine

This study examined whether tolerance or dependence develops to the effects of the low-efficacy μ opioid agonist nalbuphine on schedule-controlled responding. In untreated pigeons responding under a fixed ratio (FR)-20 schedule of food presentation, nalbuphine, naltrexone, morphine, fentanyl, etonitazene and enadoline decreased response rates. Naltrexone (0.1-10.0mg/kg) did not antagonize the rate-decreasing effects of nalbuphine. In a separate group of pigeons, chronic nalbuphine treatment (1.0-56.0mg/kg/day) did not alter the sensitivity of pigeons to the rate-decreasing effects of nalbuphine or naltrexone. In pigeons treated with 56.0mg/kg/day of nalbuphine, dose-effect curves for μ and kappa agonists were shifted 3- to 10-fold to the right of dose-effect curves determined prior to chronic treatment. The rate-decreasing effects of nalbuphine did not appear to be mediated by opioid receptors, as evidenced by the inability of naltrexone to antagonize nalbuphine and the lack of tolerance development. Although chronic nalbuphine altered the sensitivity to the rate-decreasing effects of μ and kappa agonists, there was no change in sensitivity to naltrexone. To the extent that increased sensitivity to antagonists is indicative of dependence, these data suggest that opioid dependence does not develop to nalbuphine.     

The novel kappa-opioid receptor agonist TRK-820 has no affect on the development of antinociceptive tolerance to morphine in mice

The effects of the novel kappa-opioid receptor agonist 17-cyclopropylmethyl-3,14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl)acrylamido+ ++]morphinan hydrochloride (TRK-820) on the development of antinociceptive tolerance to morphine were investigated in mice and compared with those of trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)-cyclohexyl) benzenacetamide methane sulfonate hydrochloride (U-50,488H), a well-defined exogenous kappa-opioid receptor agonist. Morphine (1. 25-20 mg/kg, s.c.) produced a dose-related antinociceptive effect in the 51 degrees C warm-plate test. Daily treatment with morphine (10 mg/kg, s.c.) resulted in the development of antinociceptive tolerance. The development of antinociceptive tolerance to morphine was dose-dependently suppressed by the co-administration of U-50, 488H (1-10 mg/kg, s.c.) with morphine, but not TRK-820 (0.003-0.03 mg/kg, s.c.). These results suggest that TRK-820-sensitive kappa-opioid receptor subtypes may not be involved in modulating the development of antinociceptive tolerance to morphine.     

Riluzole decreases the abstinence syndrome and physical dependence in morphine-dependent mice.

The effects of the antiglutamatergic agent, riluzole, were examined on the antinociceptive action of morphine, on the induction of physical dependence, and on the expression of the abstinence syndrome to the opiate in mice. Morphine was administered as a single dose (200 mg/kg) of a slow-release preparation. Acute and chronic administration of riluzole decreased the analgesic response to morphine, the intensity of abstinence behavior (administered 30 min before a dose of naloxone), and the development of physical dependence (repeatedly administered during the period of chronic morphine treatment).     

Attenuation of morphine tolerance and dependence by aminoguanidine in mice

The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.     

Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study

AIMS: The coadministration of subantinociceptive doses of oxycodone with morphine has recently been shown to result in a synergistic antinociceptive effect in rats. The present study was aimed to investigate the possibility that coadministration of morphine and oxycodone can produce a similar synergistic effect in humans exposed to an experimental model of cold pressor test (CPT). METHODS: The enriched enrollment design was used to exclude 'stoic' and 'placebo responders' in a single-blind fashion. 'Nonstoic', placebo 'nonresponder' female volunteers (n = 30) were randomly assigned to receive 0.5 mg kg(-1) oral morphine sulphate, 0.5 mg kg(-1) oral oxycodone hydrochloride, and the combination of 0.25 mg kg(-1) morphine sulphate with 0.25 mg kg(-1) oxycodone hydrochloride, 1 week apart from each other, in a double-blind crossover design. Latency to pain onset (threshold), pain intensity (VAS), and pain tolerance (time until removal of the hand from the water) were measured six times over a 3-h period, subsequent to the administration of each medication, and were used to assess their antinociceptive effect. RESULTS: The combination produced a significantly higher effect on latency to pain onset than that of morphine alone [difference in mean postbaseline value 2.2; 95% confidence interval (CI) 0.48, 3.9; P = 0.01] but the effect was nonsignificantly smaller that that of oxycodone alone. Similarly, the effect of the combination on pain tolerance was significantly larger than that of morphine alone (combination difference 8.4; 95% CI 2.5, 14.3; P = 0.007), whereas oxycodone alone caused a nonsignificantly larger effect than that of the combination treatment. Comparisons of pain magnitude failed to show any significant differences between the three treatments. CONCLUSIONS: These results indicate that at the doses tested, morphine and oxycodone do not produce synergistic antinociceptive effects in healthy humans exposed to the CPT.     

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.     

Dextromethorphan differentially affects opioid antinociception in rats

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the mu-opioid receptor agonists morphine (5 mg kg(-1), s.c.), meperidine (25 mg kg(-1), s.c.) and codeine (25 mg kg(-1), s.c.), and the kappa-opioid agonists nalbuphine (8 mg kg(-1), s.c.) and U-50,488H (20 mg kg(-1), s.c.) were studied using the tail-flick test in male Sprague-Dawley rats. Coadministration of DM (20 mg kg(-1), i.p.) with these opioids was also performed and investigated.The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.It was found that DM potentiated the antinociceptive effects of some mu-opioid agonists but not codeine or kappa-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine).The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.     

Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence

ZC88 is a novel non-peptide N-type voltage-sensitive calcium channel blocker synthesized by our institute. In the present study, the oral analgesic activity of ZC88 in animal models of acute and neuropathic pain, and functional interactions between ZC88 and morphine in terms of analgesia, tolerance and dependence were investigated. In mice acetic acid writhing tests, ZC88 (10-80 mg/kg) administered by oral route showed significant antinociceptive effects in a dose-dependent manner. The ED50 values of ZC88 were 14.5 and 14.3 mg/kg in male and female mice, respectively. In sciatic nerve chronic constriction injury rats, mechanical allodynia was ameliorated by oral administration of ZC88 at doses of 14, 28 and 56 mg/kg, suggesting ZC88 relieved allodynic response of neuropathic pain. When concurrently administered with morphine, ZC88 (20-80 mg/kg) dose-dependently potentiated morphine analgesia and attenuated morphine analgesic tolerance in hot-plate tests. ZC88 also prevented chronic exposure to morphine-induced physical dependence and withdrawal, but not morphine-induced psychological dependence in conditioned place preference model. These results suggested that ZC88, a new non-peptide N-type calcium channel blocker, had notable oral analgesia and anti-allodynia for acute and neuropathic pain. ZC88 might be used in pain relief by either application alone or in combination with opioids because it enhanced morphine analgesia while prevented morphine-induced tolerance and physical dependence.     

Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats

The goals of this study were to evaluate the effects of pretreatment by orexin receptor-1 antagonist on the development of morphine tolerance and physical dependence in rat. Animals were rendered dependent on morphine by subcutaneous (SC) injection of morphine sulfate (10 mg/kg) at set intervals of 12 h for 10 days. Just before the morphine administration, the animals received SB-334867, a selective orexin receptor 1 (OXR1) antagonist. To assess morphine tolerance, the antinociceptive responses of morphine were measured using the warm-water tail immersion test before and after its administration. On day 11, naloxone was injected 2 h after morphine administration and the physical dependence evaluated by quantifying/scoring naloxone-precipitated withdrawal signs for 30 min. The effect of chronic SB-334867 on locomotion was carried out by calculating the number of grid crossings as a measure of locomotor activity. Our findings demonstrated that although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal including diarrhea, teeth chattering, jumping, and defecation. Administration of SB-334867 alone or in a chronic co-administration with morphine failed to change locomotor activity. These results suggest that the activation of OXR1 might be involved in the development of morphine tolerance and dependence.     

The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys

The reinforcing effects of intravenously delivered cocaine, alfentanil, morphine, heroin, nalbuphine, or buprenorphine were evaluated in four rhesus monkeys before, during, and after daily administration of 3.2 mg/kg morphine. Morphine was given 21 h prior to measures of the reinforcing effects of each of the drugs. No changes in the potency of cocaine or the high efficacy mu agonist alfentanil were detectable during the period of chronic morphine administration. Small (1/2-1) log unit decreases in the reinforcing potency of intermediate efficacy mu agonists morphine and heroin occurred during chronic morphine administration. Larger decreases in both the potency and effectiveness of low-efficacy mu agonists nalbuphine and buprenorphine developed during this time. These data suggest that the amount of tolerance that develops to the reinforcing effects of opioids depends on the efficacy of the drugs used to maintain responding.     

Minocycline can delay the development of morphine tolerance,but cannot reverse existing tolerance in the maintenance period of neuropathic pain in rats

Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time‐points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats’ mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre‐administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation contributes to the morphine tolerance of SNL rats in the maintenance period of neuropathic pain, and that minocycline delays the development of morphine tolerance, but does not reverse existing morphine tolerance during the maintenance period of neuropathic pain in rats. These findings might be useful for clinical pain management.