Naloxone inhibits and morphine potentiates the adrenal steroidogenic response to ACTH

The administration of morphine to hypophysectomized rats potentiated the steroidogenic response of the adrenal cortex to exogenous adrenocorticotrophic hormone (ACTH) in a dose-dependent fashion. Conversely, the opiate antagonist naloxone inhibited the adrenal response to ACTH. Naloxone pretreatment also antagonized the potentiating effect of morphine on ACTH-induced steroidogenesis in a dose-dependent manner. Neither morphine nor naloxone, administered to hypophysectomized rats, had any direct effect on adrenal steroidogenesis. These adrenal actions were stereospecific since neither the (+)-stereoisomer of morphine, nor that or naloxone, had any effect on the adrenal response to ACTH. The administration of human beta-endorphin to hypophysectomized rats had no effect on the adrenal corticosterone concentration nor did it alter the response of the adrenal gland to ACTH. These results indicate that morphine can potentiate the action of ACTH on the adrenal by a direct, stereospecific, dose-dependent mechanism that is prevented by naloxone pretreatment and which may involve competition for ACTH receptors on the corticosterone-secreting cells of the adrenal cortex.     

Analgesia and decrement in operant performance in socially defeated mice: Selective cross-tolerance to morphine and antagonism by naltrexone

During a social confrontation between a resident and an intruder mouse, only the submissive or defeated intruder shows an opioid-mediated analgesia to which tolerance develops. We investigated the altered morphine responsiveness after different kinds of social experiences. Mice were assessed for performance of operant behavior under the control of a fixed ratio schedule of positive reinforcement as well as for the tail flick response to a heat stimulus before and after one or five consecutive social confrontations. The dose-effect curves for morphine's suppression of schedule-controlled behavior were closely similar before and after defeat in a single or in five social confrontations. However, the concurrently measured response to pain in the tail flick assay produced morphine dose-effect curves that were shifted to the right after defeat in one or five social confrontations. Four to six times higher doses of morphine were necessary to produce analgesia in mice that were defeated in five social confrontations. Naltrexone (1 mg/kg, ip) antagonized the suppressive effects of morphine (10 mg/kg, ip) on rate of responding and the analgesic effects. Naltrexone also blocked the development of analgesia in mice that were defeated for the first time in a social confrontation, but did not prevent the suppressive effects on rate of responding. Specific social experiences such as defeat in a social confrontation appear to alter endogenous opioid process that mediate analgesia; these processes differ from those that suppress positively reinforced behavior. The differential development of morphine tolerance to the analgesic effects, but not the rate-decreasing effects as well as the differential naltrexone antagonism of both effects may indicate the involvement of opioid and non-opioid mechanisms.     

Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception

Cannabinoids and opiates inhibit pain, in part, by activating the periaqueductal gray (PAG). Evidence suggests this activation occurs through distinct mechanisms. If the antinociceptive mechanisms are distinct, then cross-tolerance between opioids and cannabinoids should not develop. This hypothesis was tested by measuring the antinociceptive effect of microinjecting morphine into the ventrolateral PAG of rats pretreated with the cannabinoid HU-210 for two days. Male Sprague-Dawley rats were injected twice a day for two days with vehicle (0.4 μL), morphine (5 μg/0.4 μL), HU-210 (5 μg/0.4 μL), or morphine combined with HU-210 into the ventrolateral PAG. Repeated injections of morphine caused a rightward shift in the morphine dose-response curve on Day 3 (i.e., tolerance developed). No tolerance was evident in rats pretreated with morphine combined with HU-210. In rats pretreated with HU-210 alone, morphine antinociception was enhanced. This enhancement was blocked by pretreating rats with the cannabinoid receptor antagonist AM-251, and it also disappeared when rats were tested one week later. Acute microinjection of HU-210 into the PAG antagonized morphine antinociception, suggesting that HU-210-induced enhancement of morphine antinociception is a compensatory response. As hypothesized, there was no evidence of cross-tolerance between morphine and HU-210. In fact, cannabinoid pretreatment enhanced the antinociceptive effect of microinjecting morphine into the ventrolateral PAG. These findings suggest that alternating opioid and cannabinoid treatment could be therapeutically advantageous by preventing the development of tolerance and enhancing morphine antinociception.     

The effect of stress and adrenalectomy on morphine analgesia and naloxone potency in mice.

Pretreatment of mice with a single injection of corticosterone increased the potency of naloxone in antagonising the antinociceptive effect of morphine measured 3 h later. Pretreatment with morphine also induced a dose-dependent increase in naloxone potency. Co-administration of corticosterone with a low dose of morphine further augmented the potency of naloxone, but in combination with a higher dose of morphine it failed to cause any further potentiation of naloxone potency. Restraint stress for 1 h also caused an increased in naloxone potency when tested 3 h later, and this was further enhanced when tacrine 5.0 mg/kg was administered immediately after stress. Administration of atropine sulphate 2.0 mg/kg s.c. immediately before restraint abolished the effect of stress in potentiating the naloxone potency. Adrenalectomy sensitised mice to the antinociceptive effect of morphine. Although adrenalectomy only partially interfered with the development of increased naloxone potency after pretreatment with morphine, the augmenting effect of tacrine on naloxone potency was completely abolished. Adrenalectomy did not alter the incidence of jumping precipitated by naloxone in morphine-pretreated mice. Both restraint and corticosterone reduced the withdrawal jumping. It is concluded that the stress component of morphine is only partly responsible for the induction of increase in naloxone potency. There is an apparent interaction between central cholinergic mechanisms and stress in the induction of this increased naloxone potency. The phenomenon of increased naloxone antagonism may not be related to the development of acute dependence on morphine.     

Changes in the sensitivity of smooth muscle to neurotransmitter during acute morphine treatment and its association with analgesia

Acute in vivo administration of morphine to mice produced dose- and time-dependent subsensitivity to acetylcholine in ileum and supersensitivity to norepinephrine in vas deferens. These responses were specific to the agonist as potassium chloride-induced responses were not altered. A correlation was observed between the analgesia and the sensitivity changes produced by morphine. The sensitivity changes were mediated through opiate receptors as naloxone antagonised the effect of morphine.     

Enhancement of stress-induced analgesia in adrenalectomized mice: Its reversal by dexamethasone

Adrenalectomy significantly increased the level of analgesia induced by room temperature swimming in mice, as revealed by a hot-plate test. This augmentation of antinociceptive action of stress was abolished by dexamethasone pretreatment. Involvement of pituitary opioids in modulating post-stress pain sensitivity in mice is suggested.     

2-Deoxy-D-glucose analgesia: influences of opiate and non-opiate factors

Acute administration of 2-deoxy-D-glucose (2-DG), an antimetabolic glucose analogue induces a powerful analgesia which adapts following repeated administration. 2-DG analgesia displays significant cross-tolerance with morphine, and like morphine analgesia, is potentiated in hypophysectomized rats. The present study examined further the role of opiates in 2-DG analgesia by examining whether the opiate antagonist, naloxone, would affect 2-DG analgesia, and whether ineffective doses of 2-DG and morphine would interact in a synergistic fashion to induce analgesia. Nociceptive thresholds were measured by the flinch-jump test. Naloxone doses of 1, 5, 10 and 20 mg/kg were all ineffective in reducing significantly 2-DG (600 mg/kg) induced pain threshold elevations. Naloxone failed to attenuate 2-DG (350 mg/kg) analgesia whether administered before or after the 2-DG injection. On the other hand, simultaneous administration of sub-analgesic doses of 2-DG (200 mg/kg) and morphine (2.5 mg/kg) summated to produce significant analgesia. This, 2-DG analgesia is similar to opiates in its tolerant and summative actions, yet dissimilar in that naloxone is ineffective in reversing its effects.     

Social conflict analgesia: Studies on naloxone antagonism and morphine cross-tolerance in male DBA/2 mice

It has recently been reported that male mice exhibit pronounced analgesia in response to attack from aggressive conspecifics. Although several studies indicate that this reaction can be blocked by opiate antagonist pretreatment, unequivocal evidence of opioid involvement is very much more limited. In the present study, the phenomenon of conflict analgesia has been studied in male DBA/2 intruder mice following exposure to a criterion level of attack from aggressive BKW residents. Our findings indicate that this analgesia is (1) blocked and reversed by naloxone (2) unaltered by methyl naloxone, except at high doses (75 mg/kg) and (3) fully cross-tolerant with morphine. This profile confirms and extends earlier findings with B6AF₁ mice, indicating that the opioid mediation of this biologically-relevant form of environmental analgesia is not strain specific.     

Similar antagonism of morphine analgesia by MIF-1 and naloxone in Carassius auratus

Prolyl-leucyl-glycinamide (MIF-1), the C-terminal tripeptide of oxytocin, and naloxone were administered intracranially (IC) to goldfish (Carassius auratus) in doses of 0.001, 0.01, 0.1, 1.0 and 10.0 mg/kg and compared to a diluent control group for their ability to reduce the effects of morphine (30 mg/kg IC) in an assay measuring analgesia to electric shock. Threshold levels of pain were determined by the voltage necessary to produce an agitated swimming response (ASR). Both MIF-1 and naloxone were found to significantly reduce the analgesic effects of morphine when compared to the diluent control group. Similar dose-response curves in an apparent sine-wave pattern were noted with both MIF-1 and naloxone when comparisons were made both at 20 minutes after administration of morphine and over the entire 150 minutes of the experiment. The results support the evidence that MIF-1 can act as an opiate antagonist.     

Influence of prazosin and clonidine on morphine analgesia,tolerance and withdrawal in mice

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (₂-adrenoceptor agonist) and prazosin (₁-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another ₁-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of ₂-adrenoceptors in opioid actions, also ₁-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.     

Differential effects of opiate agonists-antagonists on morphine-induced hyperexcitability and analgesia in mice

The effects of two opiate agonists-antagonists, butorphanol (4.0 and 8.0 mg/kg) and buprenorphine (0.1 and 1.0 mg/kg), were assessed on locomotor activity and analgesia in DBA/2 and C57BL/6 mice. Diferrent behavioral effects were evident in these strains, which might becharacterized by different reactions to the effects of opiates and by differences in endorphin distributions and opiate receptor populations. In particular, buprenorphine acted as an agonist-antagonist to morphine in both strains while a dissociation of buturphanol effects was evident, depending on the strain considered. The clinical implications of these findings are discussed.     

吗啡联合氯胺酮皮下自控镇痛治疗顽固性中、重度癌痛

目的观察吗啡联合氯胺酮皮下自控镇痛（PCSA）治疗顽固性中、重度癌痛的效果及安全性。方法选择60例中、重度癌痛患者,按数字表法随机分成两组（Ⅰ组和Ⅱ组各30例）,Ⅰ组采用吗啡PCSA治疗,Ⅱ组采用小剂量氯胺酮联合吗啡PCSA治疗,两组治疗后1h、24h、48h采用视觉模拟评分法（VAS）评估疼痛程度,采用t检验分析比较两组镇痛效果、采用χ^2检验分析比较两组不良反应发生情况。结果两组治疗后1h、24h、48hVAS评分差异均无统计学意义（均P〉0．05）,但Ⅱ组吗啡用量平均31．23mg明显少于Ⅰ组的56．43mg（χ^2=6．18,P〈0．05）;Ⅱ组恶心呕吐4例（13．3％）、便秘2例（6．7％）、嗜睡2例（6．7％）、皮肤瘙痒0例（0．0）,明显低于Ⅰ组的21例（70．0％）、18例（60．0％）、9例（30．0％）、8例（26．7％）（χ^2=8．96、5．63、3．32、8．67,均P〈0．05）。结论吗啡联合小剂量氯胺酮PCSA具有镇痛作用强、不良反应小等优点,适合治疗中、重度顽固性癌痛。     

Morphine effects on maternal aggression,pup care and analgesia in mice

In order to assess the respective contribution of opioid receptors to the behavioral and physiological characteristics of lactating animals, we challenged mice with morphine at different phases of the lactation period. Sensitivity to morphine's effects on aggressive behavior, pup care, pain response and body temperature were measured. Lactating mice were assigned to 1 of the 3 weeks of lactation and to 1 of 5 doses of morphine sulfate (0, 1, 3, 6, 10 mg/kg IP). After morphine administration, rectal temperature and tail flick were assessed. Behavior towards three pups was observed for 5 min, followed by an aggression test with a female intruder. Morphine significantly increased the latency to retrieve pups and decreased aggressive behavior at doses that do not decrease motoric activity. Compared to virgin mice, lactating females are less sensitive to the analgesic actions of morphine but similarly sensitive to its hypothermic properties. The fact that virgin and lactating females can be distinguished on the basis of their sensitivity to morphine-induced analgesia suggests that lactating animals undergo functionally relevant changes in opioid regulation of pain sensitivity. Furthermore, morphine's specific and potent inhibition of pup retrieval supports the hypothesis that decreased opioid peptide activity is important for the expression of certain postpartum behaviors.     

5HT1A agonist, 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT), inhibits non-opioid analgesia in defeated mice: influence of route of administration

Recent studies have suggested that anxiety may be an important factor in the non-opioid analgesic response to defeat in muroid rodents. In the present study, we have examined the influence of the 5-HT_1A receptor agonist, 8-OH-DPAT, oin basal nociception and defeat analgesia in male DBA/2 mice. Our results show that, while devoid of intrinsic activity on the mouse tail-flick assay, 8-OH-DPAT blocks the analgetic consequences of defeat. A ten-fold potency differential was observed as a function of route of injection, with minimum effective doses of 0.1 and 1.0 mg/kg for subcutaneous and intraperitoneal administration, respectively. Although further studies are required, these preliminary data support 5-HT_1A receptor involvement in the mediation of this form of adaptive pain inhibition.     

Attenuation of morphine analgesia in rats with lesions of the locus coeruleus and dorsal raphe nucleus.

The nociceptive reflex activity and analgesic effect of morphine were studied in rats using the hind paw stimulation test. The stimulation threshold was significantly increased in animals with bilateral destruction of the locus coeruleus (LC), and was reduced after lesion of the dorsal raphe nucleus (DR). LC lesions produced a selective lowering of noradrenaline (NA) content in the forebrain, while DR lesions resulted in a reduction in serotonin levels. Lesioning both LC and DR significantly reduced both NA and serotonin contents even when the stimulation threshold was not altered. Morphine produced a significant and dose-dependent elevation of the stimulation threshold in sham-operated animals, while morphine analgesia was almost completely inhibited by destruction of LC, DR and both the nuclei. These results imply that a depression of LC-mediated noradrenergic tone results in a decreased sensitivity to painful stimuli, whereas a reduction of raphe-derived serotonergic tone produces the opposite effect against LC. It is suggested, however, that both of these monoamines from the LC and DR are necessary for the analgesic effect of morphine.     

Tolerance to the analgesic,but not discriminative stimulus effects of morphine after brief social defeat in rats

One of the most prominent consequences of defeat in a social confrontation is a long-lasting tolerance-like insensitivity to the analgesic effects of opiates, even when only small short-lived changes in nociception are detectable during the acute social stress. The present experiments examined (1) which kinds of social experiences lead to morphine tolerance, (2) whether or not the morphine tolerance in defeat-experienced rats extends from the analgesic effects to the discriminative stimulus and rate-decreasing effects of morphine, and (3) how long morphine tolerance lasts after a defeat experience. After five brief social confrontations including attack and threat by a resident rat leading to submission or defeat of the intruder, the latter exhibits marked tolerance to the analgesic effects of morphine, but not to the discriminative stimulus or behaviorally suppressive effects. Changes in social housing did not alter morphine's behavioral effects. Tolerance to the analgesic morphine effects was detected for 2 months after the defeat experience, whereas the discriminative stimulus and rate-decreasing effects were closely similar to those before defeat. This pattern was seen in animals for whom discriminative stimulus training with morphine was suspended after defeat as well as in those for whom it continued. In additional defeated and non-defeated animals, morphine's effects on the acoustic startle reflex was assessed. In contrast to the tail flick reflex to a noxious heat stimulus, the acoustic startle response remained unaffected by defeat experience or by morphine (up to 30 mg/kg). The long-lasting and large degree of tolerance after brief social defeat experiences appears to be limited to the analgesic effects of morphine. Whether or not endogenous opioid peptide activity during the actual defeat may substitute for the morphine stimulus remains to be established.     

Diurnal variations in the analgesic effectiveness of morphine in mice.

Response to thermal stimulation and the analgesic effectiveness of morphine during various phases of the diurnal cycle were assessed by the hotplate method. Saline treated controls exhibited shortest reaction times during the last quarter of the light-phase and first quarter of the dark phase. Longest reaction times were recorded during the last quarter of the dark phase. Doses of 4, 8, 16, and 32 mg/kg of morphine was administered IP at the peak and trough of the pain sensitivity rhythm. The ED50 (95% C.L.) during the last quarter of the light phase was found to be 14.60 (10.6-20.0) mg/kg while during the last quarter of the dark phase the ED50 was found to be 5.85 (4.5-7.7) mg/kg. In a second experiment, independent groups of ten mice each were injected SC with 8 mg/kg of morphine at three hr intervals over a 48 hr test session. Peak analgesic activity was obtained in the group injected during the last quarter of the dark phase while minimal analgesic effectiveness was obtained during the third quarter of the light phase. Central administration of morphine via the intraventricular route yielded the same relationship, i.e., maximal analgesic effectiveness during the last quarter of the dark phase.     

Comparison of subcutaneous and spinal subarachnoid injections of morphine and naloxone on analgesic tests in the rat

Small catheters were chronically implanted subdurally in the rat so that repeated microinjections could be made into the subarachnoid space at the lumbar area. Morphine, injected intrathecally (i.th.) produced analgesia as measured by the tail-flick test at doses $\text{1}\text{100}$ of those by the subcutaneous (s.c.) route. Analgesia from i.th. morphine was reversed by either i.th. or s.c. injected naloxone. The dose of naloxone by the i.th. route was about $\text{1}\text{30}$ of that by the s.c. route. However, i.th. injection was no more effective than s.c. injection of naloxone in reversing analgesia produced by s.c. injection of morphine. When [³H]-labelled naloxone was injected s.c. or i.th. in the above experiment of morphine antagonism, there was a more rapid entry of the labelled material in the brain by the i.th. route of administration. The results raise questions on the relative importance of the spinal mechanism of analgesia produced by s.c. injections of morphine. Analgesia was also measured by the tail-shock vocalization test in which morphine producd a dose-dependent elevation of shock threshold at s.c. doses above those prolonging tail-flick latencies. Morphine injected i.th. at doses above those which elevated tail-flick latency produced hypersensitivity, hyper-reflexia, and convulsive seizure of the hindquarters. The spinal analgesic effect of morphine, when administered localy, appears to have a low ceiling of efficacy.     

Different mechanisms are involved in the respiratory depression and analgesia induced by neurotensin in rats

The tridecapeptide neurotensin (NT), injected intracerebroventricularly in rats, induced a naloxone-insensitive and dose-dependent analgesia (tail-flick test), the ED50 being 3.22 nmol/animal. Higher doses induced a dose-dependent respiratory depression, mostly accounted for by a reduction of frequency; the ED50 for this action was 144.6 nmol/animal. In contrast to analgesia, the respiratory depression was antagonized by naloxone, suggesting the possibility that NT and opioid systems might interact at the level of respiration-related nuclei.     

A genetic analysis of morphine-induced running and analgesia in the mouse

A genetic analysis of morphine-induced analgesia and activity was conducted in mice belonging to the strains BALB/cJ, C57BL/6J, DBA/2J and to their F1 and backcross progenies. The results support previous findings showing that a negative correlation is evident between these two behavioral measures and support that their mode of inheritance is characterized by dominance or partial dominance. The biometric analysis conducted on the parental, F1 hybrid and backcross populations indicates very clearly that the effects of morphine are genetically determined.