Naloxone reversal of morphine elicited hyperactivity

When naloxone is administered during morphine elicited hyperactivity, hyperactivity is reversed and hypoactivity occurs in its place. The present experiment tested the hypothesis that this effect is the result of morphine induced supersensitivity to naloxone. Two groups of hamsters received equivalent pretreatment with 15 mg/kg morphine (Groups M/M and M/S) for three days while a third group received saline (Group S/S). During subsequent testing one group received a morphine injection (Group M/M) while the others received saline (Groups M/S and S/S) before being placed in running wheels for a three hour session. Two hours later half the animals in each group received an injection of 0.4 mg/kg naloxone and half received saline. Naloxone produced hypoactivity in animals running under the influence of morphine (Group M/M), but neither in those with an equivalent history of morphine pre-treatment (Group M/S), nor in saline controls (Group S/S). These results are inconsistent with the hypothesis under test, but congruent with a modified dual-action hypothesis.     

Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers

Effect of four calcium channel blockers (CCBs) belonging to different chemical classes, alone and in combination with morphine was investigated on two models of pain sensitivity, i.e. formalin and tail flick tests in mice. All the studied CCBs, i.e. diltiazem, flunarizine, nimodipine and verapamil inhibited formalin-induced pain responses; however, with verapamil, though there was a trend towards a reduction of paw-licking response to formalin, it was not found to be statistically significant. In contrast, none of the CCBs affected the tail flick latency at any of the doses studied. Morphine, a mu-receptor agonist exerted a significant analgesic effect in formalin as well in tail flick tests. Pretreatment with all CCBs significantly enhanced the analgesic effect of morphine in both tests of nociception. Further, concomitant administration of one of the CCBs, diltiazem with morphine prevented the development of tolerance to the latter. However, combination of diltiazem with morphine, like morphine alone was found to be ineffective in morphine tolerant animals. Results, thus, show that CCBs produced an analgesic effect of their own in formalin-induced tonic pain and potentiated the analgesic activity of morphine. They also modulated opioid-induced tolerance.     

Comparison between naloxone reversal of morphine and electrical stimulation induced analgesia in the rat mesencephalon

Comparisons were made between the efficacy of naloxone to reverse analgesia induced by electrical stimulation (SPA) of the periaqueductal gray matter and analgesia induced by microinjections of morphine into the same brain region. Naloxone at 1 or 10 mg/kg was ineffective in antagonizing SPA during the first two minutes post-stimulation. Although some antagonism did appear 3–5 minutes after stimulation, the effect was neither consistent nor dose-dependent. Morphine, on the other hand, was antagonized in a dose-dependent and complete fashion by naloxone. The assumption that similar mechanisms underlie both opiate and electrical stimulation induced analgesia is discussed.     

Naloxone blockade of acupuncture analgesia: endorphin implicated.

Electroacupuncture in awake mice produced analgesia to noxious heat stimuli causing a 54% increase in latency to squeak. Subcutaneous naloxone completely abolished this acupuncture analgesia implicating endorphin. Naloxone injections in control mice caused a 17% hyperalgesia suggesting that “normal” mice also release endorphin. These results imply that endorphin is released at a low basal rate in “normal” mice, and at a much higher rate during acupuncture.     

Footshock induced analgesia in mice: its reversal by naloxone and cross tolerance with morphine

Using the abdominal constriction response as the criterion for analgesia, mice tested immediately after a period of footshock showed a significant analgesic response compared with non-footshocked controls. Footshock induced analgesia could not be elicited in mice that had been made tolerant to morphine or in mice that had been pretreated with the narcotic antagonist naloxone. It is concluded that footshock induced analgesia in the mouse is due to the release of endogenous opioid peptides.     

Microwave-induced and pharmacological suppression of somatic pain under conditions of the formalin test in mice

We examined pain-related behavioral reactions and non-pain behavioral manifestations in mice under conditions of the formalin test. Levels of analgesia induced by i.p. injections of analgin, microwave irradiation of an antinociceptive acupuncture point (AP), E-36, or combined application of the above factors were measured. The duration of the pain behavioral reaction (licking of the injured limb) decreased due to irradiation of the AP with microwaves and to injection of 8.3 mg/kg analgin by 24.3% and 53.8%, on average, respectively. Combination of injection of analgin in a smaller dose (4.2 mg/kg) and microwave irradiation of the AP suppressed manifestations of the pain behavioral reaction by 43.4%. Thus, combination of pharmacologically induced analgesia with the action of microwaves on the antinociceptive AP allows one to significantly decrease the doses of analgesic preparations necessary to provide a full-level analgesic effect; in such a way, side effects of the respective drugs can be weakened. Neirofiziologiya/Neurophysiology, Vol. 38, No. 1, pp. 46–51, January–February, 2006.     

Naloxone increases pain perception in rats and mice.

Rats and mice manifest hyperalgesia when treated with low doses of naloxone. These doses are sufficient to block morphine analgesia. The results are consistent with the hypothesis that there is physiological release of an endogenous opioid which modulates pain sensitivity.     

Naloxone reversal of the pentobarbital induced blockade of ovulation in the rat

The effect of naloxone, an opiate antagonist, on the pentobarbital induced suppression of gonadotrophin secretion and subsequent ovulation was studied. Two injections of naloxone, the first at 13.00 h and the second, given simultaneously with an ovulatory blocking dose of pentobarbital at 13.30 h, partially reversed the inhibitory effect of the barbiturate. However, if the first injection of naloxone was given with pentobarbital at 13.30 h and a second at 14.30 h, then the opioid antagonist had no such effect. Naloxone administered alone, enhanced gonadotrophin secretion and increased the number of ova shed. These findings support the view, that endogenous opioids may exert an inhibitory influence on central neural processes involved with ovulation.     

Naloxone antagonism of phenoxybenzamine antinociception in the mouse tail stimulation test.

Phenoxybenzamine was antinociceptive in the mouse tail electrical stimulation assay (ED50, 36.8 mg/kg) with a peak effect at $\text{2}\text{1}\text{2}$ hours after subcutaneous injection. Naloxone antagonized this antinociception action of phenoxybenzamine in a dose-related manner. Dose-ratio analysis of naloxone's antagonism of phenoxybenzamine antinociception gave a pA₂ value of 6.15, similar to that found for the benzomorphinan mixed agonist-antagonists. This is in agreement with the sodium response ratio found for phenoxybenzamine, 4.3, in $\text{in vitro}$ assays of phenoxybenzamine inhibition of ³H-naloxone binding to mouse brain homogenate (5). These findings suggest that phenoxybenzamine binds to the opiate receptor both $\text{in vivo}$ as well as $\text{in vitro}$ in a manner similar to the mixed agonist-antagonists.     

Delayed onset of single dose tolerance to morphine analgesia

Rats received either 20 mg/Kg of morphine sulfate I.P. or 5 μgm of morphine sulfate microinjected into the periaqueductal gray area of the brain. The analgesic effect of the morphine was determined by comparing pre- and postinjection tailflick latencies. To test for tolerance following a single injection, the procedure was repeated 6, 12 or 24 hours after the first injection and tests. Tolerance was not observed 6 hours after the original injection, tolerance was observed at 12 hours and increased tolerance was present at 24 hours. Single dose tolerance to morphine appears to develop slowly over a period of several hours and during much of this time, the amount of opiate present in the brain was insufficient to produce analgesia. Similarity between central and peripheral administration suggests a central mechanism of single dose tolerance.     

Naloxone inhibits the plasma epinephrine response to ACTH but not to 2-deoxy-D-glucose in rats

Intravenous injection of (1-24) ACTH and 2-deoxy-d-glucose (2DG) stimulated the plasma epinephrine and norepinephrine levels in pentobarbital-anesthetized male rats. Naloxone, a specific opiate antagonist, inhibited the plasma epinephrine response to ACTH but not to 2DG. Norepinephrine release induced by ACTH or 2DG was not affected by naloxone. These results suggest that the opioid peptidergic synapse might be involved in the ACTH- but not in the 2DG-induced epinephrine release.     

Control of severe pain with sustained-release morphine tablets v. oral morphine solution.

Recently a sustained-release morphine sulfate tablet (MS Contin [MSC]) was introduced in Canada. In a randomized double-blind crossover trial we compared MSC given every 12 hours with a morphine sulfate solution (MSS) given every 4 hours to 17 patients suffering from chronic severe pain. After titration of the morphine dosage to optimize the analgesic effect, each patient received 10 days of therapy with either MSC or MSS, then 10 days of therapy with an equal daily dose of the other formulation. Both preparations provided effective pain control, with minimal side effects. There was no significant difference between MSC and MSS in pain scores on a visual analogue scale (VAS), severity scores for tiredness and nausea, amount of supplemental morphine needed for break-through pain or patient preference. The plasma morphine concentrations tended to be greater during treatment with MSC. The study had an 89% probability of detecting a clinically significant difference in VAS pain scores. We conclude that an individualized, twice-daily regimen of MSC is as effective as MSS given every 4 hours for control of severe pain. The twice-daily regimen has several advantages: it provides for an uninterrupted night''s sleep, it is substantially more convenient than the six doses per day required with MSS, and it should help reduce both medication errors and noncompliance.     

Enhancement of morphine analgesia after acute and chronic haloperidol.

In the male rats haloperidol pretreatment caused an enhancement of morphine analgesia. After chronic haloperidol the analgesia enhancing effect of haloperidol was observed up to 10 days after its discontinuation. No analgesia was present in the haloperidol treated rats not given morphine.     

Attenuation of morphine analgesia by serum from morphine-treated rabbits.

We have previously shown that repeated s.c. implantation of rabbits with pellets containing morphine or certain other narcotics evokes production of a serum morphine-binding component that has the characteristics of an immunoglobulin. We have, in the study reported here, given rabbit anti-morphine pellet serum (anti-MP) to rats i.v. at a dose equal to 20% of their blood volume. Effects on morphine analgesia as measured by the hot plate were studied following a 5 mg/kg dose of morphine. The anti-MP serum and an antiserum to a morphine-protein conjugate both significantly attenuated the analgesic response to morphine on the first day after serum treatment when compared to results in rats given control rabbit serum. Subsequent testing of the same rats (on Days 2, 9, and 48) with no additional serum treatment showed no differences in response.     

Dynorphin-A-(1–13) antagonizes morphine analgesia in the brain and potentiates morphine analgesia in the spinal cord

Intrathecal injection of subanalgesic doses of morphine (7.5 nmol) and dynorphin-A-(1–13) (1.25 nmol) in combination resulted in a marked analgesic effect as assessed by tail flick latency in the rat. The analgesic effect of the composite dynorphin/morphine was dose-dependent in serial dilutions so that a composition of 1/8 of the analgesic dose of dynorphin and 1/3 that of morphine produced an analgesic effect equipotent to full dose of either drug applied separately. The analgesic effect induced by dynorphin/morphine mixture was not accompanied by motor dysfunction and was easily reversed by a small dose (0.5 mg/kg) of naloxone. Contrary to the augmentatory effect of dynorphin on morphine analgesia in the spinal cord, intracerevroventricular (ICV) injection of 20 nmol of dynorphin-A-(1–13) exhibited a marked antagonistic effect on the analgesia produced by morphine (120 nmol, ICV). The theoretical considerations and practical implications of the differential interactions between dynorphin-A-(1–13) and morphine in the brain versus spinal cord are discussed.