Intraventricular Injection Of Morphine Research Articles

Response durations encode nociceptive stimulus intensity in the rat medial prefrontal cortex

We examined whether the medial prefrontal cortex (mPFC) encodes nociceptive stimulus intensity by applying mechanical pressure stimulation, for 2 s at 50, 100, or 300 g constant force (gf) to the tails of urethane-anesthetized rats. In a total of 1208 neurons sampled, 242 (20.0%) were responsive to mechanical stimuli. One hundred thirteen of the 242 (46.7%) were mechanical high threshold neurons (nociceptive specific neurons, NS; threshold ≥100 gf), and 35 (14.5%) exhibited a graded increase in excitator responses to a stepwise increase in stimulus intensity (wide dynamic range-like neurons, WDR-L). These 148 response discharges persisted during stimulation followed by post-stimulus discharges. The nociceptive response duration of NS neurons, but not discharge frequency, was reduced dose-dependently by intraventricular injection of morphine (0.3, and 30 μg/3 μl). Different doses of morphine may set the stimulus intensity at relatively different brain activity levels. Thus, the NS neurons used the response duration as a sensory transduction code. In WDR-L neurons, the response duration, but not always the firing frequency, was linearly related to stimulus intensity. The WDR-L neurons in the mPFC encoded stimulus intensity with response duration, although the coding method is not likely to be the same as that of sensory discriminating WDR cells in the primary somatosensory cortex. Both types of mPFC neurons encode nociceptive (absolute or relative) stimulus intensity and transform the information into the temporal duration of the next stage of pain-related modulation in animal behavior.

Morphine-induced effects on the hypothalamic stimulation-evoked emotional/behavioral reactions and peculiarities of abstinent syndrome in adult and old rats

Experiments were carried out on adult young (6- to-9-month-old) and old (28- to-30-month-old) rats. The effects of a single i.p. injection of morphine on self-stimulation of the lateral hypothalamic region and on active avoidance responses evoked by stimulation of the ventromedial hypothalamic nucleus were studied. In a separate series of the experiments we studied age-related specificities of the abolition syndrome after a course of intraventricular injections of morphine. In most old rats single injections of morphine resulted in intensification of self-stimulation, while in most adult rats such injections suppressed this reaction. In old animals injections of morphine resulted in more pronounced increases in the threshold and latency of the active avoidance responses, as compared with similar changes in adult rats. Natural abolition of a 15-day-long course of injections of morphine resulted in the development of a characteristic abstinent syndrome that was more intensively manifested in old rats. Our results show that “hedonic” and anti-aversive effects of morphine increase with aging; this phenomenon probably facilitates the development of morphine dependence in old organisms.

The reduction of antinociceptive effect of morphine administered intraventricularly is correlated with the decrease of serotonin release from the spinal cord in streptozotocin-induced diabetic rats

1. 1. The antinociceptive effect of morphine (25 μg) administered into the 3rd ventricle was significantly attenuated in streptozotocin-induced diabetic rats as measured by the tail-flick assay. 2. 2. The release of serotonin (5-HT; 5-hydroxytryptamine) from the spinal cord caused by intraventricular injection of morphine (25 μg) was significantly reduced in streptozotocin-induced diabetic rats. 3. 3. No differences of 5-HT contents of the spinal cord (lumbar cord) between streptozotocin-induced diabetic- and vehicle-treated rats were found. 4. 4. It is concluded that the reduction of antinociception produced by intraventricular injection of morphine in streptozotocin-induced diabetic rats might be, at least partly, due to the decrease of 5-HT release from the spinal cord.

Intrathecal DSP4 selectively depletes spinal noradrenaline and attenuates morphine analgesia

The noradrenergic neurotoxin DSP4 was injected intrathecally into the lumbar spinal subarachnoid space of the rat. After 10 days, dose-response curves for tail-flick inhibition were determined for both intraperitoneal and intraventricular injections of morphine. In rats pretreated with DSP4, the analgesic effect of morphine given either intraventricularly or intraperitoneally was significantly attenuated. The noradrenaline and 5-hydroxytryptamine contents in the brain-stem and the spinal cord were also measured. Intrathecal DSP4 depleted noradrenaline in the spinal cord but not in the brain-stem. Neither brain-stem or spinal cord 5-hydroxytryptamine was affected by DSP4.

Evidence for a spinal site at which opioids may act to inhibit the milk-ejection reflex.

Morphine was injected into the lumbar subarachnoid space of anaesthetized lactating rats (7-10 days post partum) to examine its effect on the milk-ejection reflex at a spinal level. Although the delay until the first milk-ejection response to the suckling of hungry pups was variable (3-60 min) the subsequent responses occurred at regular intervals of 7.5 +/- 0.4 min; milk-ejection responses were detected by measurement of intramammary pressure and by the characteristic behaviour of the pups. Injection of morphine (4-50 micrograms) via a cannula inserted into the spinal subarachnoid space inhibited reflex milk ejection in a dose-related manner without affecting the sensitivity of the mammary gland to exogenous oxytocin (1 mu., i.v.); injection extradurally was without effect. The opiate antagonist naloxone (10 micrograms), when injected intrathecally, did not significantly alter the pattern of reflex milk ejection or the amplitude of the intramammary pressure response, but prevented the inhibitory effect of morphine when administered with the opiate. Pethidine (250 and 400 micrograms) also inhibited the milk-ejection reflex. It is unlikely that the effect of spinal administration of morphine occurred as the result of the transportation to a supraspinal site since release of oxytocin evoked by intraventricular injection of hypertonic sodium chloride (3 mol/l) was blocked by intraventricular injection of morphine (4 micrograms) but not by a much larger dose (40 micrograms) injected intrathecally.

An Experimental Model for Deafferented Pain in Cats

The existence of the opioid-mediated pain inhibiting system has been well demonstrated. Facilitation of this system by administration of analgesic drugs, such as morphine or by electrical stimulation provides relief of excess pain but not of deafferented pain (thalamic or suprathalamic pain or phantom limb pain). This experiment clearly demonstrates that the suppressive effect of this opioidmediated system is exerted only on the nociceptive neurons in the subnucleus caudalis of the spinal trigeminal nucleus (STNcd), but not on the sustained neuronal hyperactivity provoked by the deafferentation of the peripheral trigeminal nerve. Preliminary studies using 16 adult cats ascertained STNcd located from obex to 2 mm caudally, and an electrophysiological study elicited nociceptive neurons distributed 3-4 mm lateral to the midline. Gasserian ganglion of the left side was totally coagulated through a subtemporal extradural approach, and it was found that a definitive neuronal hyperactivity could be observed from about 10 days after the denervation. The experiment was performed using another 13 adult cats, which were unilaterally (left side) denervated. The longest survival period of the cats was 63 days after the denervation. Forty-three neurons were identified in the STNcd of the intact (non-denervated) side, the majority of which (40 neurons) being wide dynamic range neurons. Twenty-two neurons were identified in the STNcd of the denervated side, 12 of which (55%) showing sustained high amplitude firings with no correlation to noxious stimuli (denervation hyperactivity). Such spontaneously remarkable hyperactive neurons were never detected in neurons in the intact side. Intraventricular injection of morphine or enkephalinamide, or electrical stimulation of periaqueductal gray apparently and significantly suppressed the nociceptive neuronal firing of the intact side. By contrast denervation hyperactivity was not affected. These results are compatible with the clinical experience that only excess pain but not deafferented pain is relieved by various procedures to facilitate the opioid-mediated system. From these experimental confirmations, it can be postulated that there is a close relationship between the deafferentation hyperactivity provoked in this experiment and the so-called “deafferented pain”.

Exploration and motor activity after intraventricular ACTH, morphine and naloxone

Intraventricular injection of morphine (5 μg) and ACTH (2.5 μg) reduced the time spent head-dipping and the number of head-dips made by rats during a 10-min trial in a holeboard. These effects were reversed by naloxone (2.0 mg/kg, i.p.), in spite of the fact that naloxone alone also reduced these measures of exploration. None of the drugs or drug combinations tested significantly reduced locomotor activity. The results are discussed in relation to the action of ACTH on opiate receptors.

Effects of morphine on one-trial appetitive learning

Rats given intraventricular injections of morphine before and after a single training trial on a water-finding task performed significantly better on a retention test 24 hours later than rats given Ringer's injections instead of morphine either before or after the training trial, and significantly better than rats given Ringer's before and after the training. Tial. The effect of morphine was interpreted as a retroactive strengthening of associations that the rats had formed during the training trial. The phenomenon suggests a possible model for understanding certain positively reinforcing actions of morphine.

Generalization of [DAla 2]-enkephalinamide but not of substance P to the morphine cue

Rats were trained to discriminate morphine (7.5 mg/kg, IP) from saline in a two bar positively reinforced lever pressing paradigm on a FR4 schedule. Morphine (IP) showed a naloxone reversible dose-related generalization to the training dose. [DAla 2]-Methionine enkephalinamide (DAE) at 1 mg/kg and Substance P (SP) at 0.1 and 0.25 mg/kg showed vehicle appropriate responding after IP injection. DAE (5 mg/kg) disrupted responding completely; SP (0.5 and 0.1 mg/kg) disrupted responding in 50% of the rats. The disruption caused by IP injection of DAE was not naloxone reversible. Intraventricular injection of morphine (5 μg/rat) and DAE (5 μ/rat) produced generalization to the opiate cue. The effect of DAE was reversed by naloxone (1 mg/kg, SC). SP (500 and 750 ng/rat, IVT) produced saline-like responding; 1 μg/rat disrupted responding completely. These data demonstrate that morphine and enkephalin, but not Substance P, share similar discriminative properties.

On the central sites for the antinociceptive action of morphine and fentanyl

The inhibition by morphine and fentanyl of a nociceptive response, the licking reaction elicited by electrical stimulation of the tooth-pulp, was studied in rabbits. Both drugs were injected into the entire ventricular system, and into its separate parts and morphine was applied to definite brain structures. Spread of the applied drug was examined autoradiographically, using 14C-labelled morphine. Intraventricular injection of morphine was 500–1000 times more effective than intravenous injection. The onset of action was much slower than after systemic application; this latency is interpreted as being caused by the slow permeation of morphine to the receptor areas in the periventricular structures. Injection into separate parts of the ventricular system did not inhibit the nociceptive reaction when the spread of substance was restricted to one or both lateral ventricles. Inclusion of the third ventricle in the area of distribution resulted in only a slight increase in effectiveness. Application of the drugs into the aqueduct and into the fourth ventricle induced a complete inhibition of the nociceptive reaction. When morphine spread into the surrounding of the cisterna cerebellomedullaris (with exclusion of ventricular system) no effect was observed. Uni- or bilateral microinjection of morphine into various diencephalic and mesencephalic periventricular structures induced a pronounced inhibition of the nociceptive reaction. In at least one part of these experiments, however, morphine may have acted indirectly, by spreading to caudal parts of the ventricular system. The most effective sites of the antinociceptive action of morphine-like substances were situated in the fossa rhomboides and structures near it. Autoradiographical studies showed the sites for the antinociceptive action of morphine to be located in the ventricular wall of these regions at a depth of about 1–2 mm. Diencephalic sites of action were of minor importance, at least when the licking reaction was used as test. The functional structures involved in the drug effects are discussed.