Intragastric administration of cyclo(Leu-Gly) inhibits the development of tolerance to the analgesic effect of morphine in the rat

The effect of intragastric administration of cyclo(Leu-Gly), a cyclic dipeptide derived from melanotropin release inhibiting factor (Pro-Leu-Gly-NH2), on the development of tolerance to the analgesic effect of morphine in the rat was determined. The tolerance to morphine in the rat was induced by subcutaneous implantation of four morphine pellets during a 3-day period. The rats which served as controls were implanted with placebo pellets. The analgesic response to a challenge dose of morphine was determined by the tail-flick test. The tail-flick latencies were determined before and then every 30 min for 180 min. The analgesic response was computed by determining the area under the time-response curve. Implantation of morphine pellets resulted in the development of tolerance as evidenced by decreased analgesic response to morphine in morphine pellet implanted rats as compared to placebo pellet implanted rats. Chronic intragastric administration of cyclo(Leu-Gly) (4 to 16 mg/kg) inhibited the development of tolerance to morphine. A dose of 8 mg/kg of cyclo(Leu-Gly) completely blocked the tolerance to morphine. The study provides for the first time evidence that intragastric administration of a cyclic peptide can inhibit the development of tolerance to morphine, and that effective neuropeptides and their analogs can be developed as potential drugs to inhibit opiate-induced tolerance.     

The effects of a hypothalamic peptide factor,MIF and its cyclic analog on tolerance to haloperidol in the rat

The effects of the hypothalamic peptide, ProLeuGlyNH₂ (MIF) and its analog, cyclo (LeuGly) (CLG) on the development of tolerance to haloperidol were investigated in male Sprague-Dawley rats. Chronic oral administration of haloperidol (1.5 mg/kg/day) for 21 days resulted in the development of tolerance to its pharmacological effects. A dose of haloperidol (3 mg/kg ip) exhibited an absence of cataleptic as well as hypothermic response in chronically haloperidol treated rats. Subcutaneous administration of MIF or CLG (2 mg/kg each) daily one hour prior to haloperidol injection blocked the haloperidol-induced tolerance as evidenced by the appearance of both the cataleptic and hypothermic responses. It is concluded that the hypothalamic peptide hormone, MIF may be important in regulating chronic effects of neuroleptic drugs.     

Orexin receptor type-1 antagonist SB-334867 inhibits the development of morphine analgesic tolerance in rats

Herein the effect of orexin receptor type-1 antagonist SB-334867 on the development of tolerance to analgesic effects of morphine was studied in rats. To incite tolerance, morphine sulfate was injected intraperitoneally (i.p., 10mg/kg) once a day for 7 days. The tail flick test was used to evaluate antinociceptive effects of the morphine. A selective OxR1 receptor antagonist, SB-334867, was microinjected (i.c.v.) into the right cerebral ventricle (10 μg/10 μl) immediately before each morphine injection. Repeated morphine application resulted in tolerance to morphine analgesic effects as a decreasing trend during 7 days. Also, repeated administration of SB-334867 (i.c.v.) alone was without significant effect on the nociception as compared to control. Microinjection of SB-334867 prior to each morphine injection inhibited the development of tolerance, so that the analgesic effects of morphine were significantly higher in SB-334867 plus morphine treated rats than that of vehicle plus morphine treated ones on days 4-7. It is concluded that orexin receptor type-1 might be involved in the development of tolerance to morphine analgesic effects.     

Endothelin receptor antagonists restore morphine analgesia in morphine tolerant rats

Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was measured by determining analgesic response (tail-flick latency) and hyperthermic response to morphine sulfate (8 mg/kg, subcutaneously (s.c.)) in placebo and morphine pellet implanted rats. The maximal tail-flick latency in morphine pellet-vehicle treated rats (7.54 s) was significantly lower (P<0.05) when compared to placebo pellet-vehicle treated rats (10s), indicating that tolerance developed to the analgesic effect of morphine. In separate sets of experiments, ET antagonists, BQ123 (10 microg, intracerebroventricularly (i.c.v.)) and BMS182874 (50 microg, i.c.v.) were administered in placebo and morphine tolerant rats. BQ123 was injected twice daily for 7 days and once on day 8. BMS182874 was administered only on day 8. Morphine (8 mg/kg, s.c.) was administered 30min after BQ123 or BMS182874 administration. It was found that both BQ123 and BMS182874 potentiated morphine analgesia in placebo and morphine tolerant rats. BQ123 potentiated tail-flick latency by 30.0% in placebo tolerant rats and 94.5% in morphine tolerant rats compared to respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo tolerant rats and 66.7% in morphine tolerant rats. Morphine-induced hyperthermic effect was also potentiated by BQ123 and BMS182874. The duration of analgesic action was also prolonged by BQ123 and BMS182874. The effect of BMS182874 was less as compared to BQ123. BQ123 and BMS182874 are selective ET(A) receptor antagonists. Therefore, it is concluded that ET(A) receptor antagonists restore morphine analgesia in morphine tolerant rats.     

Attenuation of morphine tolerance and dependence by alpha-melanocyte stimulating hormone(alpha-MSH).

Repeated administration of morphine resulted in significant reduction of its analgesic potency. If 0.1 mg/kg α-MSH was coadministered, the tolerance development was attenuated, 1 mg/kg MIF (MSH release inhibiting factor), given simultaneously with morphine, did not affect tolerance. Injecting, however, MIF 1 hour prior to the daily opiate treatment resulted in accelerated development of tolerance supposedly by lowering the plasma α-MSH level at the time of morphine administration. Of the morphine abstinence symptoms the naloxone-induced jumping in morphine pretreated mice could not be modified either by α-MSH coadministration or by MIF pretreament, but the withdrawal body weight loss was found to be diminished by the former and increased by the latter peptide. The possible role of α-MSH in preventing the development of tolerance to the analgesic effect of endogenous opioid peptides is discussed.     

Dissociation of tolerance to the analgesic and hypothermic effects of morphine by using thyrotropin releasing hormone

The effects of thyrotropin releasing hormone (TRH) on tolerance to the analgesic and hypothermic effects of morphine were determined in male Swiss Webster mice. The tolerance to morphine was induced by SC implantation of a morphine pellet containing 75 mg morphine free base for 3 days. Subcutaneous injections of TRH (4 mg/kg) twice a day inhibited tolerance to the analgesic effect of morphine, as evidenced by a greater degree of analgesia in TRH treated mice as compared with similarly treated vehicle injected controls. The same treatment, however, failed to modify tolerance to the hypothermic effect of morphine. These effects were produced with alterations in brain or plasma levels of morphine. It is concluded that tolerance to the two pharmacological effects of morphine may involve separate mechanism.     

The involvement of midbrain astrocyte in the development of morphine tolerance

Aims

Systemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine.

Main methods

Mice were treated with morphine (10 mg/kg, s.c.) or vehicle once a day for 5 days. Pentoxifylline (an inhibitor of glial activation; 20 mg/kg, i.p. or 50 and 100 μg/mouse, i.c.v.) was administered 30 min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5 nmol/mouse, i.c.v.) was administered 10 min before and 10 h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method.

Key findings

The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5 days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre-treatment with pentoxifylline or flavopiridol.

Significance

We demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine.     

Effects of fluoxetine and LY 367265 on tolerance to the analgesic effect of morphine in rats

Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. The aim of this study was to investigate effects of fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, and LY 367265, an inhibitor of the 5-HT transporter and 5-HT2A receptor antagonist, on tolerance induced to the analgesic effect of morphine in rats. The study was carried out on male Wistar Albino rats (weighing 170-190 g). To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After last dose of morphine, injected on day 4, morphine tolerance was evaluated. The analgesic effects of fluoxetine (10 mg/ kg; i.p.), LY 367265 (3 mg/kg; i.p.) and morphine were considered at 30-min intervals by tail-flick and hot-plate tests. The results showed that fluoxetine and LY 367265 significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effects were obtained 30 min after administration of fluoxetine and 60 min after administration of LY 367265. In conclusion, we observed that co-injection of morphine with fluoxetine and LY 367265 increased the analgesic effects of morphine and delayed development of tolerance to morphine analgesia.     

Prevention of development of tolerance and dependence to opiate in mice by BR-16A (Mentat), a herbal psychotropic preparation.

Chronic treatment with BR-16A (20-500 mg/kg) followed by saline on days 1 to 9 failed to produce any significant change in tail-flick latency from the saline-pretreated group in mice. Repeated administration of BR-16A(20-500 mg/kg) for 9 days however, attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). BR-16A (20-500 mg/kg) also suppressed, in a dose-dependent manner, the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal on day 10 of testing.     

Effect of methamphetamine on the development of acute morphine tolerance and dependence in mice

The effect of methamphetamine on morphine analgesia (tail-flick assay) was studied in non-tolerant mice and in mice made acutely tolerant to morphine following a single injection of 100 mg/kg morphine. The analgesic potency of morphine was increased in non-tolerant and tolerant mice to the same extent by 3.2 mg/kg methamphetamine (3.3 and 4.4 fold increases, respectively). In contrast, the ED50's for morphine analgesia and naloxone-precipitated jumping in mice pretreated with either 100 mg/kg morphine or both morphine and 3.2 mg/kg methamphetamine were not significantly different, indicating that methamphetamine had no effect on the development of acute morphine tolerance and dependence. Although methamphetamine had no effect on the development of acute tolerance to morphine, 4-day pretreatment with methamphetamine produced cross-tolerance to morphine analgesia. However, cross-tolerance to morphine was not accompanied by enchanced sensitivity to naloxone.     

The effect of oxytocin and fragment (MIF-I) on the development of tolerance to hypothermic and hypnotic action of ethanol in the rat

The daily pretreatment of rats with oxytocin (OXY) or MIF-I prior to ethanol (Et-OH) administration markedly altered the alcohol tolerance when tested on the fifth day of treatment. OXY (800 and 2400 nmole/kg SC) and MIF (800 nmole/kg SC) inhibited the development of tolerance to the hypnotic effect of Et-OH. MIF at this dose also inhibited the tolerance to the hypothermic effect. Only OXY in the dose of 800 nmole/kg suppressed hypothermia in an acute experiment with Et-OH and produced by itself hypothermia after acute administration (2400 nmole/kg). The tolerance to this last effect developed after four days of peptide treatment. The results indicate that OXY and MIF-I can influence the processes of development of tolerance to some central depressive effects of Et-OH in rats.     

Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa

Mitragynine is an indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa. We previously reported the morphine-like action of mitragynine and its related compounds in the in vitro assays. In the present study, we investigated the opioid effects of 7-hydroxymitragynine, which is isolated as its novel constituent, on contraction of isolated ileum, binding of the specific ligands to opioid receptors and nociceptive stimuli in mice. In guinea-pig ileum, 7-hydroxymitragynine inhibited electrically induced contraction through the opioid receptors. Receptor-binding assays revealed that 7-hydroxymitragynine has a higher affinity for micro-opioid receptors relative to the other opioid receptors. Administration of 7-hydroxymitragynine (2.5-10 mg/kg, s.c.) induced dose-dependent antinociceptive effects in tail-flick and hot-plate tests in mice. Its effect was more potent than that of morphine in both tests. When orally administered, 7-hydroxymitragynine (5-10 mg/kg) showed potent antinociceptive activities in tail-flick and hot-plate tests. In contrast, only weak antinociception was observed in the case of oral administration of morphine at a dose of 20 mg/kg. It was found that 7-hydroxymitragynine is a novel opioid agonist that is structurally different from the other opioid agonists, and has potent analgesic activity when orally administered.     

Co-administration of dextromethorphan during pregnancy and throughout lactation significantly decreases the adverse effects associated with chronic morphine administration in rat offspring.

In this study, we have focused our investigation of the facts whether co-administration of a NMDA antagonist dextromethorphan (DM) with morphine during pregnancy and throughout lactation could prevent the adverse effects associated with chronic morphine administration in rat offspring. Adult female Sprague-Dawley rats were randomly separated into four groups and were received subcutaneous injection of either saline, morphine, morphine + dextromethorphan or dextromethorphan twice a day and progressively increased 1 mg/kg at 7-day intervals from a beginning dose of 2 mg/kg for both morphine and dextromethorphan. The rats were mated between days 7 and 8. Administration of drugs was continued during pregnancy. After rat offspring were born, the doses of morphine or dextromethorphan injected into the maternal rats were increased by 1 mg/kg every two weeks till the offspring were 30 day old. The results showed that mortality of morphine group is much higher than control group. The offspring of morphine group weighed significantly less than control group on postnatal day 14 (p14), p30 or p60. The antinociceptive effect of morphine on p14 rats was reduced in the morphine group and indicated the development of morphine tolerance. The hippocampal NMDA receptor densities have been shown decreased on p14 rats. The precipitated withdrawal symptoms were assessed on p7 rats. Rats in morphine group showed greater frequency of abdominal stretch and wet dog shake in 2 hr than control group. On the other hand, co-administration of DM with morphine effectively prevented all these adverse effects of morphine to the offspring rats. DM co-administered with morphine also partially prevented the development of morphine tolerance in maternal rats. If this effect of dextromethorphan is applied to clinical pregnant patients with morphine addiction or chronic pain, it will have a great value for the benefit of their children.     

Study the mechanisms of U-50,488 to prevent the development of morphine tolerance in guinea pigs

Previously we have shown that low dose of [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride] (U-50,488) could prevent the development of morphine tolerance in guinea pigs. In the present study we tried to investigate the role of glutamate and nitric oxide in this process. Male Hartley guinea pigs (200-300 g) were chronically treated s.c. with either saline or morphine (15 mg/kg) or morphine + U-50,488 (0.003 mg/kg) twice a day for 7 days. Antinociceptive activity was assessed by hot-plate test on the first, fourth and seventh day. Spinal cord slices (450 microm) were prepared 30 min after drug treatment on eighth day and [3H] glutamate and nitric oxide (NO) released were determined. We found that coadministration of U-50,488 (0.003 mg/kg) suppressed the development of morphine tolerance to antinociceptive effect as we reported before. The percentage of in vitro spinal release of [3H] glutamate by 100 microM morphine was significantly higher in the chronic morphine group than the control group. On the other hand, coadministration of U-50,488 with morphine for 7 days blocked this effect significantly. The basal NO level released from the spinal cord slices was significantly higher in chronic morphine group but not in chronic (morphine + U-50,488) group. In vitro morphine (100 microM) increased the NO level in control group and chronic (morphine + U-50,488) group and also further increased NO in chronic morphine group. From the NMDA-displaced [3H] glutamate binding in guinea pig spinal cord, we found that the Bmax decreased in chronic morphine group but not in the chronic (morphine + U-50,488) group. In conclusion, chronic morphine treatment may activate the NMDA receptors by increasing the release of glutamate which causes the increase of synthesis and release of NO and following uncertain mechanisms to induce the development of morphine tolerance. And the mechanisms of U-50,488 to prevent the development of morphine tolerance may involve the inhibition of glutamate released by chronic morphine and also the decrease of NO induced by chronic morphine.     

The development and reversal of the tolerance to morphine in the longitudinal smooth muscle-myenteric plexus preparation of the guinea pig

Chronic treatment with morphine results in a reduction in the potency of morphine in the longitudinal smooth muscle-myenteric plexus of the guinea-pig ileum. Implantation of morphine pellets leads to the development of tolerance to the inhibitory effects of morphine upon neurogenic contractions of this preparation. Tolerance develops within 24 hours, peaks between days 4 and 7 and disappears by day 14. A similar time course for the development of tolerance to the inhibitory effects of 2-chloroadenosine is also seen in these same morphine-tolerant preparations. The rate of reversal of morphine tolerance was assessed after the removal of the morphine pellets four days after implantation. In this situation, tolerance to the effects of morphine were maintained for at least 24 hours, were partially reversed at day 2 and were totally reversed by day 4. The delay in the development and reversal of the effect are consistent with the fact that chronic treatment with morphine evokes an adaptive sensitivity change.     

Effect of Bacopasides on acquisition and expression of morphine tolerance

Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A₃, Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance.     

The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180-210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), N(G)-nitro-L-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide-cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.     

Modification of morphine-induced change in striatal (3H)-spiroperidol binding and stereotype behavior by cyclo(Leu-Gly)

Recent reports from our laboratories have indicated that the peptide cyclo(Leu-Gly), an analog of MIF (Pro-Leu-Gly-NH₂), administered prior to chronic exposure to morphine, prevents the development of both analgesic tolerance and some signs of physical dependence. The same peptide treatment also prevented the development of morphine-induced increases in certain behavioral responses to the dopamine agonist apomorphine. The present study investigated behavioral (stereotypy) and neurochemical receptor changes (specific (³H)-spiroperidol binding) occuring in the rat striatal dopamine (DA) system following chronic morphine treatment with and without prior cyclo(Leu-Gly)administration. While chronic morphine treatment (s.c. 5 pellet implant for 3 days, each pellet contained 65 mg morphine free base) did not alter the total number of high-affinity striatal (³H)-spiroperidol binding sites (28 fmol/mg tissue), it did increase the affinity of the receptor for the ligand (K_D decreased from 40 to 24 pM). Cyclo(Leu-Gly) (8 mg/kg) prevented the morphine induced increase in dopamine receptor affinity. In parallel, cyclo(Leu-Gly) prevented the increase in apomorphine-induced stereotypy which was observed in chronic morphine treated rats. The peptide alone did not alter any of the binding characteristics. These data suggest that the ability of the peptide to block the development of physical dependence induced by morphine may involve the ability of the peptide to interfere with morphine-induced changes in dopaminergic systems.     

Changes in succinic dehydrogenase activity in the central nervous system of mice during morphine dependence development, withdrawal and naloxone treatment

The possible role of succinic dehydrogenase (SD) in producing physical dependence to morphine by affecting tissue respiration was investigated in Swiss albino mice during the development of morphine tolerance through a period of addiction and naloxone withdrawal therapy. Tolerance and physical dependence were induced by injecting the mice with morphine sulfate subcutaneously at 8-hour intervals, increasing the dose from 10 mg/kg BW every 24 h for 15 days. The animals were considered to be addicted when they were able to tolerate an otherwise lethal dose of 150 mg/kg 3 times a day. Results indicated that succinic dehydrogenase was inhibited throughout the 15-day period of morphine administration and that this effect was greatest in tolerant animals. Increasing the dose and duration of treatment did not cause further decreases in enzyme activity; instead, after 15 days levels of enzyme activity increased in addicted animals compared with tolerant mice. Furthermore, morphine abstinence for 2 days, markedly increased the levels of SD activity, while 6 days of abstinence had little effect. Naloxone withdrawal at each stage was associated with increased SD activity, but the increase was significant only in tolerant mice.     

Chimeric peptide of Met-enkephalin and FMRFa induces antinociception and attenuates development of tolerance to morphine antinociception.

A synthetic chimeric peptide of Met-enkephalin and FMRFamide (YGGFMKKKFMRFa), based on MERF was synthesized. This peptide was tested for possible antinociceptive effects using the tail flick test in mice. The effect of the chimeric peptide on morphine antinociception and development of tolerance to the antinociceptive action of morphine was also investigated. The chimeric peptide produced significant, dose-dependent antinociception (40, 60 and 90 mg/kg) in the tail flick test. Pretreatment with naloxone (5 mg/kg, IP) significantly attenuated the antinociceptive effect induced by the chimeric peptide (90 mg/kg, IP), indicating involvement of an opioidergic mechanism. In combination experiments with morphine, the antinociceptive dose of the chimeric peptide (60 mg/kg, IP) potentiated morphine (7 mg/kg, IP) antinociception. A low dose of the chimeric peptide (10 mg/kg, IP), that did not produce significant antinociception on its own, also potentiated morphine antinociception. In the tolerance studies, male albino mice received twice daily injections of morphine (20 mg/kg, IP) followed by either saline (0.1 ml) or chimeric peptide (80 mg/kg, IP) for a period of 4 days. A control group received twice daily injections of saline (0.1 ml) for the same period. When tested on Day 5, tolerance to antinociceptive action of morphine (15 mg/kg, IP) was evidenced by decreased response in chronic morphine plus saline treated mice compared to control group. Concurrent administration of chimeric peptide (80 mg/kg, IP) with morphine significantly attenuated the development of tolerance to the antinociceptive action of morphine. The preliminary results of this study demonstrate that peripherally administered chimeric peptide can produce dose dependent, naloxone reversible, antinociception; potentiate morphine antinociception and attenuate morphine tolerance, indicating a possible role of these type of amphiactive sequences in antinociception and its modulation. These chimeric peptides may also prove to be useful tools for further ascertaining the role of FMRFa family of peptides in mechanisms leading to opiate tolerance and dependence.