Involvement of spinal opioid systems in footshock-induced analgesia: Antagonism by naloxone is possible only before induction of analgesia

Footshock reliably produces analgesia in rats which is mediated either by opiate or non-opiate systems. It has recently been demonstrated that a critical factor determining the involvement of endogenous opioids is the body region shocked; front paw shock produces a naloxone-reversible analgesia and hind paw shock produces an analgesia which fails to be attenuated by this opiate antagonist. The present study demonstrated that a crucial opiate site for the production of front paw footshock-induced analgesia (FSIA) exists within the spinal cord. One microgram of naloxone delivered directly to the lumbosacral cord immediately prior to shock significantly attenuated this analgesia. However, the efficacy of naloxone antagonism was order-dependent in that naloxone failed to antagonize fron paw FSIA if delivered immediately after shock; naloxone could prevent but could not reverse the analgesic state. The body region shocked was again observed to be a critical factor determining the involvement of endogenous opioids since 1 microgram of spinal naloxone failed to antagonize hind paw FSIA. These results were discussed in light of recent evidence proposing a neuromodulatory role of opioids within the spinal cord.     

Opiate vs non-opiate footshock-induced analgesia (FSIA): The body region shocked is a critical factor

Previous work has demonstrated that footshock can elicit either opiate or non-opiate analgesia. The present study has demonstrated that one critical factor determining the involvement of endogenous opioids is the body region shocked. Using 90 s shock, front paw shock produced an opiate analgesia which was significantly antagonized by as little as 0.1 mg/kg systemic naloxone and morphine tolerance. In the latter experiment, a parallel recovery of the analgesic potencies of both front paw shock and morphine was observed following 2 weeks of opiate abstinence. In contrast, hind paw shock produced a non-opiate analgesia which failed to be attenuated by 20 mg/kg systemic naloxone and showed no cross-tolerance to morphine. Since identical shock parameters were used for front paw and hind paw shock in the systemic naloxone experiments, stress per se clearly cannot be the crucial factor determining the involvement of endogenous opioids in footshock-induced analgesia. These results were discussed with respect to clinical treatments of pain which utilize somatosensory stimulation.     

Evidence for opioid and non-opioid forms of stimulation-produced analgesia in the rat

This study compares stimulation-produced analgesia (SPA) elecited from two different midline regions of the midbrain of the rat. Dorsal electrode placements were in the caudal periaqueductal gray matter; ventral placements lay within or subjacent to the dorsal raphe n. SPA thresholds were measured by the tail-flick method both during and immediately after the period of brain stimulation. Thresholds were consistently higher in the post-stimulation test. SPA from dorsal and ventral regions differed in the following ways: (1) Post-stimulation analgesia was significantly more difficult to obtain in ventral than in dorsal regions, whereas during-stimulation analgesia did not vary as a function of electrode location; (2) Although a continuous distribution of thresholds was seen for ventral placements, thresholds for dorsal placements tended to be either high or low on both during- and post-stimulation tests; (3) Naloxone (0.01–10 mg/kg) reliably elevated SPA thresholds for ventral but not dorsal stimulation placements. We conclude that different substrates of SPA lie in close proximity to one another in the medial midbrain of the rat. This portion of the midbrain appears to mediate both opioid and non-opioid mechanisms of analgesia.     

Effect of histamine and the H2 antagonist cimetidine on the growth and migration of human neoplastic gila

Histamine is known to act, at least in part, as a growth factor, as production of this neurotransmitter has been found to accelerate the rate of tissue proliferation in wound repair, embryogenesis and malignant growth. Histamine favours in vivo tumour cell proliferation via H₂ receptors. Cimetidine is an H₂ blocker and has been shown to inhibit tumour cell growth. In the present study, the growth modulating effects of histamine and cimetidine were assessed on five cell lines derived from human brain tumours of different histological types and grades of malignancy. Each cell line was treated with either cimetidine or histamine for 24 h before kinetic analyses, with PCNA, or motility assays, using Transwell migration chambers incorporating a microporous membrane, were carried out. Cimetidine significantly inhibited cell proliferation in three out of the five cell lines, which may indicate the dependence of proliferation of these cell lines on stimulation of the H₂ receptor. With regard to migration, it was observed that in the majority of cell lines, cimetidine induced migration whilst histamine inhibited it. It was concluded that the link between effects of histamine on proliferation and its effects on migration must be clarified using a larger sample of cell lines.     

Opioid and non-opioid mechanisms of footshock-induced analgesia: Role of the spinal dorsolateral funiculus

Exposure to inescapable footshock causes either an opioid or non-opioid mediated analgesia in the rat depending on the temporal parameters of its administration. Lesions of the spinal dorsolateral funiculus significantly reduce both the opioid and non-opioid forms of this footshock-induced analgesia. Thus, these two neurochemically discrete pain-inhibitory systems appear to depend on the integrity of the same descending path, one known to be activated by morphine and by analgesic brain stimulation.     

Enhancement of footshock-induced analgesia by spinal 5,7-dihydroxytryptamine lesions

The analgesia induced by 30-s footshock (1 mA) is enhanced and attenuated by decreasing and increasing the extraneuronal availability of serotonin (5-HT), respectively. In the present work we have shown the effect to be mediated by spinal 5-HT systems as the response was increased by depletion of spinal but not brain 5-HT following injection of 5,7-dihydroxytrptamine into the spinal cord or raphe magnus. Injection of 5,7-DHT into the medial raphe which depleted brain but not spinal 5-HT was without effect.     

Footshock-induced analgesia: Its opioid nature depends on the strain of rat

Previous studies have indicated that stressful footshock can induce both opioid, naloxone-sensitive, and non-opioid, naloxone-insensitive forms of analgesia, depending on stimulation parameters used with 30 min of intermittent footshock (3 mA, 1 s on, 5 s off) producing opioid analgesia and 3 min of continuous shock (3 mA) producing non-opioid analgesia. Using a local strain of Charles River (CR)-derived rats we conducted a parametric investigation of footshock-induced analgesia applying both AC and DC scrambled shock ranging from 1 to 4 mA, continuous shock of 1, 3 and 5 min in duration and intermittent shock lasting 1, 3, 5, 10, 20, 30 and 80 min. All shock parameters produced potent analgesia. In no case did 10 mg/kg of naloxone block this analgesia. Varying the dose of the antagonist (0.1-10 mg/kg) and testing the animals at different points in the diurnal cycle did not result in the emergence of naloxone-sensitive anangesia. Based on the assumption that non-opioid systems may mask the activity of opioid analgesia systems, we attempted to either enhance opioid analgesia by: preventing enkephalin degradation by the use of D-phenylalanine; increasing the entry of blood-borne opioids into the brain by the use of DMSO; and the attenuation of non-opioid analgesia by the use of reserpine. In no case did a naloxone-sensitive component of analgesia emerge. To test whether the animals possess an intact opioid analgesia system, both electrical stimulation of, and injection of opiates into the periaqueductal gray (PAG) were examined. Both procedures produced analgesia which was reversed by naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glutamate-induced analgesia: Blockade and potentiation by naloxone

Injection of 0.5 μll-sodium glutamate (60 mM) into the periaqueductal gray matter of the rat resulted in a short-lived analgesia as assessed by the tail-flick method. Naloxone (1 mg/kg) attenuated glutamate-induced analgesia when injected 30 min but not 5 min before testing. Paradoxically, a higher dose of naloxone (10 mg/kg) significantly potentiated glutamate analgesia when injected 5 min but not 30 min before testing. Moreover, this higher dose also potentiated analgesia when injected 5 min prior to 12 mM glutamate, a dose of glutamate previously found to be ineffective in causing analgesia. Microinjections of either 60 mM or 1 M KCl failed to elicit analgesia, indicating the specificity of the glutamate effect. Taken together with several other lines of evidence, the present findings suggest that glutamate-induced analgesia may be mediated by processes quite different from those underlying morphine analgesia. It is further suggested that a dose-related naloxone antagonism is not a necessary criterion for assessing endogenous opioid activity.     

Effects of naloxone and hypophysectomy on electroconvulsive shock-induced analgesia

Powerful analgesia follows electroconvulsive shock in both hypophysectomized and sham-operated rats. Antagonism of this analgesia by naloxone implicates opioid peptides in its mediation, its occurrence in hypophysectomized animals implicating opioids of central nervous system rather than pituitary origin. Because naloxone only partially reduces electroconvulsive shock analgesia in hypophysectomized rats, the participation of another, non-opioid analgesia substrate also seems indicated.     

Spinal vs supraspinal actions of morphine on cat spinal cord multireceptive neurons

To examine whether morphine elicits a supraspinal mediated spinal inhibition of nociceptive transmission, several investigators have compared the effects of morphine on nociceptive transmission in animals with the spinal cord intact vs transected or cold-blocked. The results have been conflicting, possibly due to different methods of analysis. For example, some investigators have found i.v. administered morphine produces a greater percentage decrease in nociceptive transmission when the spinal cord is intact compared to the transected state. Therefore, they concluded that morphine elicits a supraspinal-mediated inhibition. Conversely, others have reported that the increase in noxious stimulus-evoked responses of dorsal horn neurons upon cold blocking the spinal cord was reduced by i.v. morphine. They therefore concluded that morphine decreases descending inhibition. We tested the effects of i.v. morphine on spinal cord multireceptive neurons in the presence and absence of descending inhibition. Using the above methods of analysis, our results were found to be consistent with their findings which indicate that the method of analysis used is critical to the interpretation reached. To determine how these calculations would be affected by a depressant effect on the spinal cord neurons only, we performed similar experiments iontophoresing gamma-aminobutyric acid (GABA) onto these dorsal horn neurons. The similarity between the morphine and GABA data suggests that the effects of systemically administered morphine on multireceptive dorsal horn neurons can be adequately explained by a spinal cord site of action.     

Stimulation-produced and stress-induced analgesia: cross-tolerance between opioid forms

Electrical stimulation of medial brainstem sites produces potent analgesia in rats that is either opioid- or non-opioid-mediated depending on the specific brain region stimulated. Footshock stress also causes opioid and non-opioid forms of analgesia in rats depending on the exact parameters of footshock administered. We now report that opioid, but not non-opioid, stress analgesia demonstrates cross-tolerance with opioid, but not non-opioid, stimulation-produced analgesia. This finding suggest that opioid forms of stimulation-produced and stress-induced analgesia share a common substrate.     

Different opioid systems may participate in post-electro-convulsive shock (ECS) analgesia and catalepsy

Administration of electroconvulsive shock (ECS) to rats results in post-ictal analgesia and catalepsy both of which can be partially reversed by the opiate antagonists, naloxone and naltrexone. Tolerance to both phenomena develops following daily ECS administrations for 10 days. However, qualitatively different patterns of tolerance development of analgesia and catalepsy are seen. Naloxone treatment prior to ECS provides partial protection against the development of tolerance to ECS-induced catalepsy but does not prevent the tolerance to post-ECS analgesia. In contrast, the long-lasting opiate antagonist, naltrexone, blocked the development of tolerance to ECS analgesia. Furthermore, the same animals that showed tolerance to the analgesic effects of repeated ECS failed to show analgesia following the administration of 10 mg/kg of morphine while naltrexone, but not naloxone, treatment prior to ECS blocked the development of cross-tolerance to morphine analgesia. A dose-response investigation of morphine's action (5, 10, 15 and 20 mg/kg) in additional animals receiving 10 daily administrations of ECS reveals that a greater tolerance to morphine's motor inhibitory effect than to its analgesic effect results from repeated ECS administration. Finally, animals receiving daily injections of either a low (10 mg/kg) or a high (100 mg/kg) dose of morphine for 10 days showed markedly attenuated post-ECS analgesia and catalepsy. However, whereas similar effects of opiate antagonists and the chronic administration of both doses of morphine were observed with post-ECS catalepsy, analgesia was least affected by naloxone (50% of control) and most affected by the chronic high dose of morphine (14% of control). Furthermore, a similar degree of tolerance to post-ECS analgesia was seen following either repeated ECS in drug-naive animals or the chronic administration of the high dose of morphine. Thus, the partial naloxone blockade of ECS analgesia and the more substantial attenuation of post-ECS analgesia seen in morphine-tolerant animals provide different estimates of opioid involvement in these phenomena. It is proposed that these results may demonstrate the involvement of different opioid systems in analgesia and catalepsy and it is suggested that more than one opioid system may also be involved in post-ECS analgesia.     

The effect of hypophysectomy on acupuncture analgesia in the mouse

Acupuncture analgesia was quantitated in the phenylquinone induced writhing test in mice. Both manual acupuncture and electroacupuncture significantly reduced the number of writhes, i.e. 47% and 51% reduction respectively. Naloxone (2 mg/kg) pretreatment abolished this antinocicpetive effect suggesting that an endogenous opiate-like substance was involved. Hypophysectomy did not alter the electroacupuncture induced inhibition of writhing. These results confirm previous reports that acupuncture causes the release of an endogenous substance(s) with opioid activity, but disagree with previous reports in that our data show that the hypophysis is not involved in the release of this endogenous opiate or in any other mechanism of acupuncture analgesia in the mouse.     

Lack of interaction between cimetidine and carbamazepine

In order to investigate a possible interaction between cimetidine and carbamazepine (CBZ) 7 otherwise healthy epileptic patients on a long-term monotherapy with CBZ were given cimetidine (1 g daily) for 7 days. No significant alterations in steady-state plasma concentration of CBZ and the 10,11-epoxide metabolite (CBZ-E) were demonstrated.     

Morphine-induced analgesia and explosive motor behavior in an amphibian

Morphine sulfate is a weak analgesic in the frog Rana pipiens pipiens, causing a slight increase in nociceptive threshold at a dose of 10 mg/kg and a pronounced increase at 100 mg/kg. Morphine-induced analgesia persists for at least 165 min and is significantly attenuated by naloxone. The analgesic doses of morphine are well below the lethal dose and are without noticeable effect on the behavior of the frogs or their responses to non-painful stimuli. Higher doses of morphine (320 and 640 mg/kg) induced a state of hyper-responsiveness to sensory stimuli similar to the explosive motor behavior induced in rats by microinjection of morphine into the periaqueductal gray.     

Analgesic effects of μ antagonists after naloxone non-reversible stress-induced analgesia

Three antagonists at the mu opiate receptor site: naloxone, naltrexone and diprenorphine, and one agonist-antagonist compound nalorphine, at doses usually not analgesic elicited analgesia in rats when administered after non-naloxone-reversible shock-induced analgesia had disappeared. The chi receptor antagonist, MR 2266, and the delta antagonist, ICI 154129, were all ineffective. This effect was no longer present when non-naloxone-reversible shock-induced analgesia was inhibited by the administration of the chi receptor antagonist, MR 2266. These results suggest that the mu opiate receptor may change its conformation under particular conditions such as continuous inescapable shock.     

Body region shocked need not critically define the neurochemical basis of stress analgesia

Both opioid and non-opioid forms of stress-induced analgesia have been demonstrated in rats, although the conditions leading to their selective activation are still being investigated. We have shown that variations in shock intensity, duration or temporal pattern can determine whether opioid or non-opioid stress analgesia occurs. Others have suggested that body region shocked is the critical determinant, analgesia from front paw shock being opioid and that from hind paw shock non-opioid. We now report that either opioid or non-opioid stress analgesia can be evoked from either front or hind paws depending only on footshock intensity when duration and temporal pattern are held constant.     

Histamine and prostanoid receptors on glial cells

Glial cells in vitro express at least two types (H₁ and H₂) of histamine receptors and three types (EP, FP, and TP) of prostanoid receptors. The receptors expressed by glial cells differ according to the cell type and source in the brain. Further-more primary astrocytes of same type derived from the same brain region are composed of heterogeneous subpopulations expressing different subsets of receptors. Fura-2 based Ca²⁺ microscopy revealed that astrocyte processes are important sites for histamine-induced Ca²⁺ signalling. Histamine and prostanoid receptors on glial cells may play important roles in the actions of histamine and prostanoids in the central nervous system. © 1994 Wiley-Liss, Inc.     

Kindling-induced changes in morphine analgesia and catalepsy: Evidence for independent opioid systems

Repeated stimulation of the amygdaloid complex in rats results in the kindling of epileptic seizures. During the process of kindling and prior to the appearance of full behavioral convulsions naloxone-sensitive changes in responsiveness to noxious stimulation occur, which disappear with repeated stimulation. When full behavioral convulsions appear, a short period of post-ictal behavioral depression (PID) can be seen immediately following convulsions. Naloxone either attenuates or completely blocks the occurrence of the PID.In order to test further the opioid nature of these phenomena, the development of tolerance to PD with repeated stimulation and the development of cross-tolerance to the analgesic and motor depressant effects of morphine were tested in kindled animals. Repeated elicitation of full behavioral convulsions resulted in a progressive decrease of PID duration across days. PID was also decreased in morphine tolerant animals. Repeated convulsions also induced cross-tolerance with both morphine analgesia and morphine-induced catalepsy. In contrast, animals tested following 10 days of amygdaloid stimulation which did not cause full behavioral convulsions to develop, showed cross-tolerance to the analgesic but not the motor depressant effect of morphine. The possibility that two different opioid systems, which are independent of one another are activated during different phases of kindling is discussed.