Potentiation Of Morphine Antinociception Research Articles

Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval

The actual time-course of morphine antinociception is shorter than what would be predicted from its elimination kinetics, suggesting the presence of an acute tolerance phenomenon. Since antagonists acting at NMDA subtype of glutamate receptors were repeatedly shown to prolong acute morphine antinociception, acute tolerance may be attributed to hyperactivity of NMDA receptors. The ability of various site-selective NMDA receptor antagonists to affect morphine antinociception (tail-flick test) was assessed in mice 30 and 120 min after acute morphine challenge. Competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid ( d-CPPene) (SDZ EAA 494; 0.1–1 mg/kg), low-affinity channel blockers 1-amino-3,5-dimethyl adamantane (memantine) (1–10 mg/kg) and 1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride (MRZ 2/579) (1–10 mg/kg), glycine site antagonists 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021) (5 or 10 mg/kg) and 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaliono(4,5-b)quinoline-5-oxide choline salt (MRZ 2/576) (1–10 mg/kg) were administered intraperitoneally (i.p.) 15 or 30 min prior to the tail-flick test (i.e., interval between injections of morphine and NMDA receptor antagonist was either 0–15 or 90–105 min). ACEA-1021, MRZ 2/576 and to the lesser extent, memantine and MRZ 2/579 enhanced morphine antinociception when tests were conducted 120 but not 30 min post-morphine. d-CPPene potentiated morphine antinociception irrespective of the interval between morphine administration and the tail-flick test. The results suggest that NMDA receptor antagonists may restore analgesic activity of morphine in acutely 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.

Modulation of morphine-induced antinociception by ibogaine and noribogaine

The potential modulation of morphine antinociception by the putative anti-addictive agent ibogaine and its active metabolite (noribogaine) was investigated in rats with the radiant heat tail-flick test. Ibogaine pretreatment (40 mg/kg, i.p., 19 h) significantly decreased morphine (4 mg/kg, s.c.) antinociception, with no effects in the absence of morphine. However, co-administration of ibogaine (1–40 mg/kg, i.p.) and morphine (4 mg/kg, s.c.) exhibited a dose-dependent enhancement of morphine antinociception. Co-administration of noribogaine (40 mg/kg, i.p.) and morphine also resulted in an increase in morphine antinociception, while noribogaine pretreatment (19 h) had no effect on morphine antinociception. The results show that ibogaine acutely potentiates morphine antinociception and that noribogaine could be the active metabolite responsible for this effect. However, the inhibitory effects of a 19 h ibogaine pretreatment, which resemble ibogaine-induced inhibition of morphine's stimulant properties, cannot be accounted for by noribogaine.

Dextromethorphan potentiates morphine antinociception, but does not reverse tolerance in rats.

The N-methyl-D-aspartate (NMDA) and cholecystokinin (CCK)-B receptors may have a role in the development and reversal of tolerance to morphine. In morphine-tolerant rats, addition of the CCK-B receptors antagonist CI 988 or the NMDA receptor blocker dextromethorphan enhanced the antinociceptive effect of morphine on the hot plate test. However, combined administration of CI 988 and dextromethorphan did not further potentiate the antinociceptive effect of morphine in tolerant rats. Dextromethorphan by itself had no effect in tolerant rats. In drug-naive rats, dextromethorphan by itself had no antinociceptive effect, but when combined with morphine or morphine and CI 988, it significantly potentiated the magnitude and duration of the effect of morphine. Thus, unlike the reversal of tolerance with CI 988 at doses that did not potentiate the effect of morphine, the antinociception observed with the NMDA antagonist in the presence of morphine in tolerant rats may not represent the reversal of tolerance, but may instead reflect the potentiation of morphine's analgesic effect by dextromethorphan.

Effect of the NMDA‐antagonist, MK 801, on benzodiazepine‐opioid interactions at the spinal and supraspinal level in rats

1. Benzodiazepines potentiate morphine antinociception at the spinal level via GABAergic mechanisms. At the supraspinal level, the inhibitory effect of midazolam on morphine antinociception cannot be easily explained by GABAA receptor activation. Since excitatory amino acids play a role in central transmission, we investigated the effect of dizocilpine (MK 801) on this interaction in spinal cord and brain. 2. In rats with an intrathecal or intracerebroventricular catheter, the mechanisms of the antinociceptive effect of benzodiazepine-morphine combinations were tested during thermal nociceptive tests. 3. The principal findings of this study were that at the spinal level, midazolam potentiation of morphine antinociception can be antagonized by the NMDA antagonist, MK 801 (10 micrograms), as assessed by hot-plate and tail-flick tests. When drugs were administered supraspinally, midazolam inhibited morphine antinociception only in the hot-plate test, an effect also inhibited by MK 801. In the tail-flick assay, midazolam failed to influence the morphine response. 4. The NMDA antagonist significantly affected midazolam antinociception at the spinal level, but was not effective following i.c.v. administration of the drugs. MK 801 had no effect on morphine antinociception after i.t. and i.c.v. administration of the drugs. 5. The paradoxical effect of midazolam on morphine antinociception and its reversal by MK 801 might be due to modulation at various levels of the neuraxis and/or modulation of different pathways mediated via both GABAA and NMDA receptor mechanisms.

Ketorolac potentiates morphine antinociception during visceral nociception in the rat.

Combinations of opioids and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to control pain in the perioperative period, yet there are no quantitative evaluations of the interaction between opioids and nonsteroidal antiinflammatory drugs during visceral nociception. This study evaluated the interaction between morphine and ketorolac during visceral nociception in the rat. The pressor response to noxious colorectal distention (80 mmHg, 20 s) was evaluated in 29 male Sprague-Dawley rats and dose-response curves were determined for intravenous morphine, ketorolac and the mixture of morphine and ketorolac. The data were interpreted using an isobolographic analysis to establish the nature of the interaction. Intravenous ketorolac alone (8-32 mg/kg) did not have a significant antinociceptive effect, whereas morphine alone (1-4 mg/kg) produced significant antinociception during noxious colorectal distention (dose yielding a 50% reduction in nociceptive response relative to baseline pressor response = 1.7 +/- 0.6 mg/kg). Isobolographic analysis of the antinociceptive interaction demonstrated a highly significant, naloxone-reversible potentiation of intravenous morphine by ketorolac in the rat during visceral nociception (P < 0.001). Ketorolac is a powerful potentiator of morphine antinociception during visceral nociception in the rat. However, intravenous ketorolac alone did not demonstrate antinociceptive properties during colorectal distention, a model of acute visceral nociception without a major inflammatory component. These data suggest that ketorolac may have a central modulatory effect on opioid pharmacology and the synergistic effect may be separate from its peripheral antiinflammatory properties. This study encourages further basic as well as clinical evaluations of the improved antinociception provided by combination therapy of opioids and nonsteroidal antiinflammatory drugs.

Intrathecal co-administration of morphine and excitatory amino acid agonists produce differential effects on the tail-flick of intact and spinal rats

Previous reports, that intrathecal morphine is more potent on the tail-flick test of acute spinal rats than intact rats, suggested that spinal opiate analgesia was attenuated by neurotransmitter release from descending pathways. To determine if this phenomenon involved excitatory amino acids (EAAs), 0.25 nm of N-methyl- d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) were i.t. co-administered with morphine to Intact and Spinal rats. NMDA potentiated morphine antinociception in Intact but not Spinal rats; AMPA had no effect in Intact rats, but significantly reduced morphine antinociception in Spinal rats. The data suggest a reciprocal descending, modulatory influence on the spinal interaction between EAAs and morphine.

Inhibition of nitric oxide synthase enhances morphine antinociception in the rat spinal cord

N G-nitro-L-arginine methyl ester (L-NAME, 400–1500μg), administered intrathecally (ith.), elicits a slight but dose-related antinociception in rats, assessed by tail-flick and paw pressure tests. L-NAME (400μg) and morphine (0.5μg) coadministered ith. elicit a profound and long-lasting antinociception, which is abolished by ith. administration of 3-morpholino-sydnonimine (SIN-1, 100μg). Hemoglobin (266μg) administered ith. also slightly potentiates morphine antinociception. These results suggest that nitric oxide (NO) is involved in spinal nociceptive events, and that the increased production of NO following the nociceptive input may diminish the efficiency of opioid antinociception in the spinal cord.

Pharmacological regulation of opioidergic antinociceptive mechanisms

Naloxone-depending potentiation of morphine antinociception by some non-opioidergic compounds between different classes of drugs was found in experiments on mice using nociceptive stimuli of different modality. This potentiation can or cannot be bound with elevation of sensitivity of opioid receptors, release of endogenous opioids or destruction of blood-brain barrier function mor morphine peripheral administration. This potentiation named as "release of functional reserve of opioid antinociceptive response" can or cannot be accompanied by an increase of breathing function depression. Taking into account the data of literature about the dissociation of analgetic positive-supporting morphine effects and also the capability of some compounds to lower the narcogenic opiates potential, the supposition about the real possibility of creating combined drugs is made.

In vivo electrochemical evidence that the tricyclic antidepressant femoxetine potentiates the morphine-induced increase in 5-HT metabolism in the medullary dorsal horn of freely moving rats

Acute administration of tricyclic antidepressants (TCAs) is known to potentiate morphine antinociception. At the medullary dorsal horn (MDH) level systemic morphine has been shown to increase serotonin (5-HT) metabolism as measured by in vivo electrochemistry in freely moving rats. Using similar electrochemical detection of 5-hydroxyindole (peak ‘3’) within the MDH, the present study investigated the effect of the specific 5-HT uptake inhibitor femoxetine on peak 3 and the effects of this TCA on changes in 5-HT metabolism induced by morphine. Acutely administered femoxetine (40 mg/kg i.p.) (i) induced a small but significant increase in peak 3 and (ii) strongly potentiated the effect of morphine (10 mg/kg i.p.) on 5-HT metabolism, this potentiation being opiate specific since simultaneous injection of naloxone (1 mg/kg i.p.) abolished the effect of morphine. These findings provide an in vivo neurochemical basis for the potentiation of morphine antinociception by TCAs. They further emphasize the importance of 5-HT bulbospinal descending pathways in morphine antinociception.

Effects of Adrenalectomy on Pharmacokinetics and Antinociceptive Activity of Morphine in Rats

The effects of adrenalectomy on the pharmacokinetics and antinociceptive activity of morphine were investigated to elucidate the mechanism of adre-nalectomy-induced potentiation of morphine antinociception in rats. Plasma concentrations of morphine were estimated specifically and serially in each rat by high performance liquid chromatography with an electrochemical detector. After the intravenous administration of 10 mg/kg morphine, the plasma half-life of morphine was significantly prolonged by adrenalectomy without any effect on the volume of morphine distribution. After the subcutaneous administration of 7 mg/kg morphine, pharmacokinetic parameters were changed by adrenalectomy in the same manner as after intravenous administration. In contrast, after the subcutaneous injection of 3.5 mg/kg morphine, adrenalectomy failed to change the pharmacokinetic parameters. The antinociceptive potency of subcutaneously administered morphine was enhanced by adrenalectomy for both doses of morphine (3.5 and 7 mg/kg). Morphine antinociception at the dose of 3.5 mg/kg, s.c, in the adrenalectomized group was equipotent with that of 7 mg/kg, s.c, in the sham-operated group, but plasma morphine concentrations for 3.5 mg/kg, s.c, in the adrenalectomized group were significantly lower than those for 7 mg/kg morphine, s.c, in the sham-operated group. These results suggest that the enhancement of morphine antinociception by adrenelectomy can not be explained by the increased morphine level alone.

Effects of adrenalectomy on pharmacokinetics and antinociceptive activity of morphine in rats.

The effects of adrenalectomy on the pharmacokinetics and antinociceptive activity of morphine were investigated to elucidate the mechanism of adrenalectomy-induced potentiation of morphine antinociception in rats. Plasma concentrations of morphine were estimated specifically and serially in each rat by high performance liquid chromatography with an electrochemical detector. After the intravenous administration of 10 mg/kg morphine, the plasma half-life of morphine was significantly prolonged by adrenalectomy without any effect on the volume of morphine distribution. After the subcutaneous administration of 7 mg/kg morphine, pharmacokinetic parameters were changed by adrenalectomy in the same manner as after intravenous administration. In contrast, after the subcutaneous injection of 3.5 mg/kg morphine, adrenalectomy failed to change the pharmacokinetic parameters. The antinociceptive potency of subcutaneously administered morphine was enhanced by adrenalectomy for both doses of morphine (3.5 and 7 mg/kg). Morphine antinociception at the dose of 3.5 mg/kg, s.c., in the adrenalectomized group was equipotent with that of 7 mg/kg, s.c., in the sham-operated group, but plasma morphine concentrations for 3.5 mg/kg, s.c., in the adrenalectomized group were significantly lower than those for 7 mg/kg morphine, s.c., in the sham-operated group. These results suggest that the enhancement of morphine antinociception by adrenelectomy can not be explained by the increased morphine level alone.

Zopiclone potentiates the antinociceptive effect of morphine in rats.

The antinociceptive effect of morphine, as determined by the tail-flick test, was dose-dependently increased by the intraperitoneal injection of zopiclone. The benzodiazepine antagonists Ro 15-1788 (flumazepil) and Ro 15-3505, when intraperitoneally injected, significantly antagonized the effect of intraperitoneal injection of zopiclone on morphine antinociception. Intrathecal injection of zopiclone potentiated morphine antinociception, while the intracerebroventricular injection of zopiclone failed to enhance morphine antinociception and the intracerebroventricular injection of flumazepil to antagonize the intraperitoneal-zopiclone-induced increase in morphine antinociception. These results suggest that benzodiazepine sites are specifically involved in the potentiating effect of zopiclone on morphine antinociception. The anatomical locations of the receptors involved seem to be at the spinal level.

Potentiation of morphine antinociception by monoamine reuptake inhibitors in the rat spinal cord

Potentiation of the antinociceptive effects of morphine by the tricyclic antidepressants was assayed in awake restrained rats using the tail-flick test. Intrathecally administered amitriptyline, desipramine or sertraline at doses that had no effect themselves (25–30 μg) potentiated a subthreshold parenteral dose of morphine (0.5 mg/kg). The morphine potentiating effect of amitriptyline was prevented by prior administration of parachlorophenylalanine (PCPA). This effect of PCPA was not restored by 5-hydroxytryptophan (5-HTP) but was restored when the animals were left for 14 days to replete. The morphine potentiating effects of amitriptyline, desipramine and sertraline were blocked by intrathecal administration of low doses of the serotonin antagonist methysergide and the α-adrenergic antagonists yohimbine and phentolamine but not by the β-adrenergic antagonist propranolol. The results are consistent with the hypothesis that the potentiation of morphine's antinociceptive effect by tricyclic antidepressants depends on activation of both spinopetal serotonin and adrenergic neurons.

Differential effects of di-isopropylfluorophosphate poisoning and its treatment on opioid antinociception in the mouse

Compounds which enhance cholinergic activity have been reported to interact with opioid drugs. We have shown, using the hot-plate test in mice that di-isopropylfluorophosphate potentiates the antinociceptive activity of alfentanil but has no effect on the activity of morphine or fentanyl. Administration of atropine and pralidoxime as a treatment for DFP poisoning does not reverse this effect, and itself potentiates morphine antinociception. The results suggest that a cholinergic/opioid interaction is dependent on the opioid studied, and may have clinical importance when opioid drugs are required in patients poisoned by irreversible anticholinesterases.

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Two inhibitors of acetylcholinesterase, physostigmine and diisopropylfluorophosphate, potentiated morphine antinociception, as measured by inhibition of the tail-flick response, in both nontolerant mice and in mice rendered tolerant to morphine by pellet implantation for three days. Although the response to morphine was modified in tolerant animals, inhibition of acetylcholinesterase did not alter the development of tolerance. Physostigmine and diisopropylfluorophosphate also caused pronounced inhibition of naloxone-precipitated withdrawal jumping; however, development of physical dependence on morphine, as measured by body weight loss during abrupt withdrawal, was not affected by the two drugs. These results suggest that some of the actions of morphine might be mediated in part by acetylcholine and, although acetylcholinesterase inhibition may modify the tolerant and dependent state, the mechanism involved primarily in their development is not materially affected.