Morphine and enkephalin: analgesic and epileptic properties.

Systemic and intracerebroventricular administration of analgesic doses of morphine resulted in large increments of spontaneous multiple unit activity in the periaqueductal gray matter of the awake rat. Intracerebroventricular injection of methionine enkephalin gave analgesia in only 8 of 19 rats, but in all 8, and in no others, increased periaqueductal multiple unit firing was also seen. These findings support the view that the periaqueductal gray matter is actively involved in endogenous mechanisms of analgesia. A striking observation was that enkephalin caused electrographic and behavioral epileptic phenomena in most animals. This observation together with other recent findings suggests that endogenous enkephalin may play some role in epileptogenesis.

Long ascending projections from substantia gelatinosa Rolandi and the subjacent dorsal horn in the rat.

Small neurons of the substantia gelatinosa Rolandi and the subjacent dorsal horn of the spinal cord have been thought to exert a direct modulatory effect only on neurons located within a distance of a few spinal segemnts. By using the technique of retorograde transport of horseradish peroxidase, however, it has been found that in the rat a significant number of these cells, particularly those of the subjacent dorsal horn, ascend many spinal segments to the lateral cervical nucleus and to the lower brainstem. These data provide an anatomic basis for a role of substantia gelatinosa Rolandi and subjacent dorsal horn cells in madulating or contributing to sensory information transmission not only in nearby segments but in far distant structures.

Characterization of chronic pain and somatosensory function in spinal cord injury subjects.

The pathophysiology of the chronic pain following spinal cord injury (SCI) is unclear. In order to study it's underlying mechanism we characterized the neurological profile of SCI subjects with (SCIP) and without (SCINP) chronic pain. Characterization comprised of thermal threshold testing for warmth, cold and heat pain and tactile sensibility testing of touch, graphesthesia and identification of speed of movement of touch stimuli on the skin. In addition, spontaneously painful areas were mapped in SCIP and evoked pathological pain--allodynia, hyperpathia and wind-up pain evaluated for both groups. Both SCIP and SCINP showed similar reductions in both thermal and tactile sensations. In both groups thermal sensations were significantly more impaired than tactile sensations. Chronic pain was present only in skin areas below the lesion with impaired or absent temperature and heat-pain sensibilities. Conversely, all the thermally impaired skin areas in SCIP were painful while painfree areas in the same subjects were normal. In contrast, chronic pain could be found in skin areas without any impairment in tactile sensibilities. Allodynia could only be elicited in SCIP and a significantly higher incidence of pathologically evoked pain (i.e. hyperpathia and wind-up pain) was seen in the chronic pain areas compared to SCINP. We conclude that damage to the spinothalamic tract (STT) is a necessary condition for the occurrence of chronic pain following SCI. However, STT lesion is not a sufficient condition since it could also be found in SCINP. The abnormal evoked pain seen in SCIP is probably due to neuronal hyperexcitability in these subjects. The fact that apparently identical sensory impairments manifest as chronic pain and hyperexcitability in one subject but not in another implies that either genetic predisposition or subtle differences in the nature of spinal injury determine the emergence of chronic pain following SCI.

Acute pain threshold in subjects with chronic pain following spinal cord injury.

Studies of pain perception in patients with chronic pain have yielded contradictory results. While several studies found that acute pain threshold is raised in chronic pain subjects, others showed that these subjects exhibit a decreased pain threshold compared to pain free subjects. The aim of this study was to further examine this topic by studying pain perception in subjects with chronic pain following partial or complete spinal cord injury (SCI). We found a significant elevation of heat-pain threshold (measured above the level of lesion) in complete SCI subjects with chronic pain (CSCIP) as opposed to complete SCI subjects without pain, incomplete SCI subjects with (ISCIP) and without chronic pain and normal controls. This elevation of pain threshold was completely reversed following a complete relief of the chronic pain by DREZ lesion. Moreover, the CSCIP exhibited significantly higher scores in the McGill pain questionnaire compared to ISCIP, indicative of a more intense chronic pain perceived by these subjects. In addition, the chronic pain below the level of spinal lesion, reported by CSCIP originated from a significantly larger body area than that of ISCIP. These results indicate that a critical level of chronic pain must be perceived in order to induce an elevation in acute pain threshold.

Clip-induced analgesia and immobility in the mouse: pharmacological characterization.

A pinch to the nape of the neck of mice, by application of a noxious clip, produces analgesia and immobility. Because both opiate and dopaminergic systems are usually implicated in analgesia and immobility, the pharmacological profile of clip-induced effects was compared to those elicited by the dopamine antagonist haloperidol, and by morphine. In addition, the effects of a series of pharmacological agents on clip-induced effects was examined. Haloperidol, but not morphine, produced immobility similar to that seen after application of the clip to the neck. Application of clip completely inhibited righting in all tests utilized. Haloperidol inhibited righting in all tests, except for inversion from a supine position. Righting from this position could also be inhibited in mice treated with haloperidol when a mild pinch, ineffective in a naive animal, was applied. Clip-induced immobility, but not analgesia, was reversed by amphetamine. Administration of the cholinergic antagonist scopolamine, but not methylscopolamine, reversed both the analgesia and immobility. Pinch-induced analgesia was as marked as that elicited by morphine but could not be reversed by the opiate antagonist naloxone. It is proposed that pinch-induced immobility is mediated by both dopaminergic and cholinergic systems. Additional unidentified systems are also involved. Analgesia, induced by a noxious pinch, can be dissociated pharmacologically from the immobilizing effect, is non-opiate in nature, and involves activation of central cholinergic synapses.

Involvement of N-methyl-D-aspartate receptors in nociception and motor control in the spinal cord of the mouse: behavioral, pharmacological and electrophysiological evidence.

The present study evaluated, using behavioral and electrophysiological methods, the involvement of the N-methyl-D-aspartate receptor in the processing of noxious information in the spinal cord of the mouse. The selectivity of the excitatory amino acid antagonists 2-amino-5-phosphonovalerate and glutamylaminomethylsulphonate was assessed behaviorally, using their ability to reverse the biting behavior elicited by intrathecal excitatory amino acid administration as a tool. 2-Amino-5-phosphonovalerate at concentrations up to 1 mM was shown to be selective for the N-methyl-D-aspartate receptor, while glutamylaminomethylsulphonate was selective for the kainate and quisqualate receptors at similar concentrations. At these concentrations, intrathecal administration of 2-amino-5-phosphonovalerate to awake mice produced significant analgesia on a battery of tests, as well as a dose-related motor impairment, while glutamylaminomethylsulphonate was without effect. Proof that 2-amino-5-phosphonovalerate exerts its effects via N-methyl-D-aspartate receptors is that glutamylaminomethylsulphonate, at concentrations which also block this receptor (greater than 1 mM), also produced analgesia and motor effects. Furthermore, N-methyl-D-aspartate, but not kainate or quisqualate, reversed the analgesic effects of 2-amino-5-phosphonovalerate. In fact, significant potentiation of analgesia could be seen with quisqualate. In accordance with the behavioral pharmacological data, topical application of 2-amino-5-phosphonovalerate onto the spinal cord of anesthetized mice significantly depressed the response of spinal sensory neurons to noxious mechanical and electrical stimulation, but did not affect the activity of neurons which showed no preferential reaction to noxious stimulation. Glutamylaminomethylsulphonate at non-analgesic concentrations was without effect. Based on these and other studies we conclude that N-methyl-D-aspartate receptor bearing interneurons participate in nociception, and that N-methyl-D-aspartate antagonists exert their analgesic and motor effect by changing the tone of spinal neural action in the spinal cord, rather than direct intervention in primary afferent transmission.

Different behavioral deficits are induced by anoxia/hypoxia in neonatal and senescent rats: blockade by MK-801.

Rats exposed on their first postnatal day to 100% nitrogen for 25 min developed hyperactivity and lower performance in passive avoidance task during development. Administration of MK-801 (0.5 mg/kg i.p.) 1 h before anoxia or (0.25 and 0.5 mg/kg) 1 h after completely reversed this behavioral impairment. Senescent rats (24-26 months) exposed to hypoxia (92% N2 + 8% O2) for 5 h failed in their performance in C.A.R., 30 days later. Pretreatment with MK-801 (1 mg/kg i.p.) completely reversed this impairment. These data suggest that activation of endogenous NMDA receptors produces different behavioral consequences in neonatal and senescent rats and that MK-801 administration close to exposure of animals to anoxia or hypoxia can prevent such damage, thus preventing behavioral impairments in postnatal as well as in senescent rats.

Different endogenous analgesia systems are activated by noxious stimulation of different body regions.

Noxious pinch of the neck and the base of the tail can produce equipotent analgesia as measured by the tail flick method. However, noxious stimulation of the neck can suppress pain responsiveness both at the site of stimulation and at sites remote from the stimulated area while noxious stimulation of the tail produces analgesia only at sites remote from the stimulated area. Thus, neck pinched animals are immobile and completely unresponsive to the noxious pinch whereas pinch to the base of the tail, which results in tail flick suppression, causes vocalization and well organized biting behavior directed at the pinched area. The analgesia elicited by noxious stimulation applied to both body regions is eliminated by spinalization, the administration of intermediate doses of barbiturates (30 and 45 mg/kg) and transection at the midcollicular, but not more rostral, brain level. Concurrent with the elimination of the analgesic effect of noxious pinch on tail flick is the emergence of responses to noxious neck pinch with vocalization and intense motor reactions now elicited by noxious stimulation of the nape of the neck. These results indicate that different analgesic systems are activated by noxious tail and neck pinch both requiring the integrity of mesencephalic structures for their normal function. Furthermore, these systems can be distinguished by their ability to produce recurrent, inhibitory, supraspinal effects on nociceptive information originating at different body regions.

Intrathecal N-methyl-D-aspartate (NMDA) activates both nociceptive and antinociceptive systems.

Injection of the excitatory amino acid N-methyl-D-aspartate (NMDA) into the spinal subarachnoid space of rats produces both hyperalgesic and analgesic effects. At lower concentrations (0.5 mM) little behavioral effect is elicited by the drug. However, brief hyperalgesia followed by several minutes of analgesia can be detected in these animals. Higher concentrations of the drug produce vocalization, caudally directed scratching and biting and hyper-responsiveness to light touch. The NMDA antagonist, arginine vasopressin, produces analgesia when injected by itself and completely reverses all effects of NMDA. NMDA-induced analgesia, but not hyperalgesia, is reversed by intrathecal administration of naloxone, methysergide and phentolamine. The analgesic effects of both agonist and antagonist are markedly potentiated by spinalization. These results suggest the involvement of NMDA receptors in both the transmission of pain and the mediation of spinal segmental pain inhibitory mechanism.

Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-D-aspartate induce permanent neural damage.

Despite extensive evidence for the neurotoxic effects of excitatory amino acids (EAA) in the brain little is known about their neurotoxic action in the spinal cord. In this study we attempted to produce differential lesions of spinal neurons by pretreating mice, intrathecally, with high concentrations of the EAA: N-methyl-D-aspartate (NMDA), quisqualate and kainate. Pharmacological, behavioral and histological consequences were examined 1, 3, 7 and, in some cases, 30 days after pretreatment. A single, intrathecal, injection of high concentrations of quisqualate and kainate but not NMDA, resulted in damage to spinal cord neurons. The highest concentrations of these agonists produced, in some animals, a massive, non-selective destruction of neurons within the lumbar spinal cord, accompanied by complete paralysis of the hindlimbs. Pretreatment with lower concentrations of intrathecal kainate or quisqualate produced damage to spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal cord to EAA, as seen from the decrease in biting behavior elicited by intrathecal EAA. The neurotoxic effects of quisqualate were completely blocked by the quisqualate/kainate receptor antagonist glutamylaminomethylsulphonate (GAMS), but not the NMDA antagonist 2-amino-5-phosphovalerate. GAMS attenuated the effects of kainate only partially.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracerebral opiates block the epileptic effect of intracerebroventricular (ICV) leucine-enkephalin.

Intracerebroventricular (ICV) injection of both enkephalin (100 micrograms) and morphine (200 micrograms produces characteristic electrographic seizures. Injection of low doses of either morphine or levorphanol into the lateral ventricle of the brain prior to the administration of epileptogenic doses of enkephalin can block the induction of such seizures. A similar trend was observed when either opiate preceded ICV morphine. Microinjections of both morphine (30 micrograms) or levorphanol (40 micrograms) into the periaqueductal gray area (PAG) or into the nucleus accumbens resulted in potent analgesia. However, only morphine injected into the nucleus accumbens was effective in blocking electrographic seizures induced by ICV enkephalin. On the basis of this and other previous findings we propose that the excitatory-epileptic and the inhibitory-antiepileptic action of opiates and opioids are mediated by two different systems. Furthermore, we propose that such systems may differ both in their anatomical distribution and in the classes of opiate receptors underlying their action.

Systemic morphine blocks the seizures induced by intracerebroventricular (i.c.v.) injections of opiates and opioid peptides.

Intracerebroventricular (i.c.v.) injections of the endorphins and of morphine in rats produce highly characteristic, naloxone sensitive, electrographic seizures. In contrast, systemic injections of morphine have been shown to exert a marked anticonvulsant effect. The present study demonstrates that systemic morphine pretreatment can prevent the occurrence of electrographic seizures injected by i.c.v. morphine, Leu-enkephalin and beta-endorphin and that the anti-epileptic effect of morphine can be reversed by naloxone. Male albino rats, previously prepared for chronic i.c.v. injections and EEG recordings, were pretreated with 0--100 mg/kg of intraperitoneal (i.p.) morphine. Thirty five minutes later morphine (520 nmol), Leu-enkephalin (80 nmol) or beta-endorphin (5 nmol) were injected i.c.v. Pretreatment with i.p. morphine blocked the occurrence of seizures induced by morphine and both endogenous opioids. Lower doses of systemic morphine (50 mg/kg) were necessary to block i.c.v. morphine seizures than the dose (100 mg/kg) necessary to block seizures induced by i.c.v. Leu-enkephalin and beta-endorphin. Naloxone (1 mg/kg) administered 25 min following 50 mg/kg of i.p. morphine and preceding the injections of i.c.v. morphine reversed the antiepileptic effect of systemic morphine. These results demonstrate the possible existence of two opiate sensitive systems, one with excitatory-epileptogenic effects and the other possessing inhibitory-antiepileptic properties. The possible relationship between these findings and the known heterogeneity of opiate receptors and opiate actions is discussed.

Tail-pinch induced analgesia and immobility: altered responses to noxious tail-pinch by prior pinch of the neck.

Noxious pinch to the scruff of the neck using a metal clip produces profound immobility and analgesia. Noxious pinch delivered to the tail fails to induce immobility and results in nociceptive behavior directed at the pinched tail. However, when administered shortly after neck-clip removal, noxious tail-pinch reinstated immobility without any nociceptive response. Prior neck-clip also enhanced the antinociception induced by the tail-pinch as measured by nociceptive response to a leg pinch. Immobility, as well as antinociception, decreased as the time interval between neck-clip removal and the tail-pinch application increased. Pharmacological manipulations which reduce nociception produced a similar alteration in the response to tail-pinch. Thus, following local injections antinociceptive doses of lidocaine to the base of the tail and systemic morphine administration tail-pinch produced marked immobility. Transection of the brain at the intercollicular level provides evidence for supraspinal involvement in post-neck pinch effects. Not only was the ability of prior neck-pinch to confer antinociceptive properties on tail-pinch abolished, but increased responsiveness to noxious tail-pinch was seen. We, therefore, propose that prior neck-pinch confers new stimulus properties on noxious pinch of other body regions resulting in an enhanced antinociceptive effect, which affects both remote regions and the site of stimulation, and the ability to induce immobility.

Spinal mechanisms of the analgesic action of electroconvulsive shock.

The present study investigated the spinal systems involved in the analgesic action of electroconvulsive shock (ECS). To identify such systems complete spinal transections and discrete lesions within the dorsal half of the spinal cord were performed. Complete spinal transection eliminated ECS analgesia totally, demonstrating that the observed analgesic effect is attributable to neural conduction. Lesions within the region of the dorsolateral funiculus (DLF) caused a pronounced, but incomplete, attenuation of ECS analgesia. Larger lesions of the dorsal aspects of the spinal cord including both the DLF and the dorsal column area did not result in further attenuation of analgesia. Thus, it appears that within the dorsal cord the area of the DLF contains the fibers mediating the antinociceptive action of ECS. Additional experiments were conducted to determine the neuromediators involved in ECS analgesia. Of a wide range of antagonists injected intraperitoneally (methysergide, phentolamine, haloperidol, diphenhydramine, naloxone, picrotoxin, theophylline and scopolamine), only methysergide produced a significant attenuation of ECS analgesia. In contrast, following intrathecal injections of antagonists a dose-related decrease of analgesia could be seen after the injections of methysergide, phentolamine and naloxone implicating spinal serotonin, noradrenaline and the enkephalins in the analgesic action of ECS. To assess further the interaction between the action of these neurotransmitter systems, we evaluated the effect of drug pair combinations on ECS analgesia. Intrathecal phentolamine + naloxone, methysergide + naloxone and methysergide + phentolamine were injected at doses that caused maximal attenuation of analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress induced analgesia: its opioid nature depends on the strain of rat but not on the mode of induction.

Reports by several investigators have shown that both opioid and non-opioid analgesia can be induced by non-pharmacological manipulations such as the administration of electric shock, and that such analgesia depends on shock parameters, the affective state of the animal and the region of the body shocked. We tested several manipulations which have been reported to induce opioid analgesia using a local strain of rats (CR). Such manipulations included the used of 30 min of intermittent footshock (3 mA, 1 s on, 5 s off), brief shock to the forepaws, transpinal electroconvulsive shock (ECS) and tail shock induced helplessness. Administration of either naloxone or naltrexone to rats of the CR strain failed to attenuate the analgesic effect of these manipulations and in some cases even enhanced analgesia. The existence of functional opioid analgesia systems in CR rats was evident from the fact that electrical stimulation of the periaqueductal gray area produced naloxone sensitive analgesia. In additional experiments we compared the analgesic effect of brief continuous (3 min) footshock, prolonged intermittent footshock (30 min) and ECS in young (less than 75 days of age) and old (greater than 75 days of age) rats of the Sabra strain. Young Sabra rats showed naloxone sensitive analgesia following all 3 manipulations while adult rats displayed analgesia which was naloxone insensitive. Furthermore, no decrement in learning, indicative of helplessness, could be demonstrated in young Sabras following 3 min of shock which induced naloxone sensitive analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Strain differences in autotomy levels in mice: relation to spinal excitability.

The consequences of combined transection of the sciatic and femoral nerves were investigated in mice of the ICR and C3HEB strains. Whereas all the animals of the C3HEB strain showed very clear self mutilatory behavior of the denervated limb (autotomy) none of the ICR mice showed autotomy. Further tests, using the hot plate and tail flick methods, show that C3HEB mice were more sensitive to noxious thermal stimuli than ICR mice. Finally, spinalization at the lumbar level revealed a markedly higher level of spinal excitability in C3HEB mice as evident from a marked decrease in nociceptive thresholds in these animals. No such threshold decrease was observed in spinalized ICR mice. The results suggest that different levels of spinal excitability underlie the susceptibility for the emergence of autotomy in mice. It is proposed that such different levels of excitability may also underlie the susceptibility for the emergence of neuropathic pain.

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.

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 administration 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 present 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.

Opiate and non-opiate aspects of morphine induced seizures.

The intraperitoneal administration of morphine hydrochloride at doses of 300 mg/kg produced analgesia, catalepsy, and electrographic spiking in rats that developed into electrographic seizure patterns after approximately 2.5 h. Whereas naltrexone (12 mg/kg) reversed analgesia and catalepsy, and diminished electrographic spiking, it precipitated electrographic seizure activity similar to that observed following intraperitoneal morphine alone. These seizures were accompanied by behavioral convulsions. No tolerance to these seizures developed with repeated paired administration of morphine and naltrexone or in morphine tolerant rats, but rather potentiation was observed. The epileptogenic effects were found to be potentiated in amygdaloid kindled rats, as well. It was concluded that morphine at these doses activates two different epileptogenic mechanisms, one mediated by opiate receptors, the other not. The possibility of the simultaneous activation of a morphine sensitive anticonvulsant mechanism is discussed.