In vivo electrochemical detection of 5-hydroxyindole within the trigeminal nucleus caudalis of freely moving rats: the effect of morphine

The trigeminal nucleus caudalis is considered the equivalent of the orofacial nociceptive system of the dorsal horn of the spinal cord. At the level of this trigeminal area (i.e. medullary dorsal horn) the transmission of noxious inputs is strongly modulated by a descending, serotonergic system mainly originating from the nucleus raphe magnus (NRM). The present study in freely moving animals reports the effect of morphine on the 5-hydroxyindole oxidation current recorded in the medullary dorsal horn. Complementary data from recordings in spinal dorsal horn in acutely anesthetized rats are also presented. A current recorded at 270–290 mV (peak ‘3’), characteristic of 5-hydroxyindoleacetic acid (5-HIAA), was measured with treated multi-fiber carbon electrodes, using differential pulse voltammetry (DPV) or differential normal pulse voltammetry (DNPV). In control rats, the amplitude of the peak remained constant for many hours. Morphine (10 mg/kg i.p.) caused a significant increase which plateaued between 35 and 80 min (mean increase: 127 ± 5 % of control values); recovery was complete by about 3 h. Simultaneous injection of naloxone (1 mg/kg i.p.) totally abolished the effect of morphine. By contrast, morphine was without effect on peak 3 recorded in the spinal dorsal horn of chloral hydrate (450 mg/kg i.p.) anesthetized rats. It is concluded that in non-anesthetized freely moving animals morphine clearly increases the metabolism of serotonin (5-HT) in the medullary dorsal horn. This finding confirms previous neurochemical data showing an increased synthesis or release of 5-HT in the spinal cord after systemic morphine or its microinjection into either the periaqueductal gray matter or the NRM, and underlines the value of in vivo electrochemistry in monitoring changes in 5-HT metabolism directly and continuously during various physiological and pharmacological procedures.     

In vivo voltammetric studies of the effect of morphine on the serotonergic system in the cat spinal cord

The purpose of the present paper is to investigate the effect of morphine on the serotonergic system through an analysis of electrochemical signals in the spinal cord of the anesthetized cat. Electrochemical signals showed a peak of 5-hydroxyindole at 280-300 mV, and were highest at a depth of 1500-2500 microns in the dorsal horn of the spinal cord. Electrical stimulation of the nucleus raphe magnus (NRM) produced an increase in the electrochemical signal. Five-hydroxytryptophan (25 mg/kg, i.v.) also enhanced the signal remarkably. Both systemic administration of morphine (1-2 mg/kg, i.v.) and microinjection (5 and 10 micrograms/microliter) of morphine into the NRM increased the signal. In conclusion, it is suggested that morphine-induced enhancement of the peak of 5-hydroxyindole contributes to the activity of the serotonergic system in the cat spinal cord.     

Effects of tianeptine on 5-hydroxyindoles and on the morphine-induced increase in 5-HT metabolism at the medullary dorsal horn level as measured by in vivo voltammetry in freely moving rats

The present study, by the use of in vivo electrochemical detection of 5-hydroxyindole (peak ‘3’) in the bulbo spinal serotonergic system at the medullary dorsal horn (MDH) level, investigated the effects of the new tricyclic antidepressant (TCA) tianeptine, which has been shown to be a specific serotonin (5-HT) uptake enhancer. It was found that acutely administered tianeptine (10 mg/kg, i.p.) induced a marked significant increase in peak 3 within the dorsal horn, an in vivo observation which is in accordance with the biochemical properties of tianeptine as studied in forebrain structures. In addition, the effect of tianeptine on the morphine-induced increase in 5-HT metabolism was investigated, by comparison with the previous data obtained with the specific 5-HT uptake inhibitor femoxetine in the MDH. It was shown that tianeptine can display additive effect with morphine (10 mg/kg, i.p.) on 5-HT metabolism at the MDH level. These results are discussed in relation to the effects of classical TCAs and the particular properties of tianeptine.     

The effect of morphine on the potassium evoked release of tritiated 5-hydroxytryptamine from spinal cord slices in the rat

The effect of morphine on the potassium (40 mM) evoked release of exogenous [3H]5-HT from slices of the dorsal spinal cord of the rat was studied. The effects of in vitro applied morphine on the slices were compared to those produced by systemic morphine applied to the animals before preparation of the slices. The in vitro application of morphine (10(-6) to 10(-5) M) did not affect the release of [3H]5-HT. By contrast, it was observed that the potassium evoked release of [3H]5-HT from the slices of the spinal cord of rats which had received 10 mg/kg s.c. of morphine 30 min beforehand was significantly increased. The effect of systemic morphine was dose-dependent (in the range of 1.5-10 mg/kg s.c.) and could be blocked by prior administration of naloxone (1 mg/kg i.m.) 2 min before the morphine. The acute administration of 10 mg/kg s.c. of morphine, which did not induce analgesia in rats rendered tolerant to morphine, did not modify the [3H]5-HT release. Higher doses of morphine, which have been shown to restore analgesia in these rats, induced an increase in the release which was significant for a dose of 100 mg/kg s.c. These results demonstrating a specific and dose-dependent increase in the potassium evoked release of [3H]5-HT from spinal dorsal cord slices after systemic administration of morphine, emphasize the role of serotonergic systems in such analgesia. The lack of effect of the drug directly applied in vitro favours a supraspinal site of action of the drug and is in good agreement with recent results in the literature.     

In vivo electrochemical evidence that the tricyclic antidepressant femoxetine potentiates the morphine-induced increase in 5-HT metabolism in the medullary dorsal horn of freely moving rats

Acute administration of tricyclic antidepressants (TCAs) is known to potentiate morphine antinociception. At the medullary dorsal horn (MDH) level systemic morphine has been shown to increase serotonin (5-HT) metabolism as measured by in vivo electrochemistry in freely moving rats. Using similar electrochemical detection of 5-hydroxyindole (peak '3') within the MDH, the present study investigated the effect of the specific 5-HT uptake inhibitor femoxetine on peak 3 and the effects of this TCA on changes in 5-HT metabolism induced by morphine. Acutely administered femoxetine (40 mg/kg i.p.) (i) induced a small but significant increase in peak 3 and (ii) strongly potentiated the effect of morphine (10 mg/kg i.p.) on 5-HT metabolism, this potentiation being opiate specific since simultaneous injection of naloxone (1 mg/kg i.p.) abolished the effect of morphine. These findings provide an in vivo neurochemical basis for the potentiation of morphine antinociception by TCAs. They further emphasize the importance of 5-HT bulbospinal descending pathways in morphine antinociception.     

Morphine analgesia and newly synthesized 5-hydroxytryptamine in the dorsal and the ventral halves of the spinal cord of the rat

In the rat, morphine (5 mg/kg, s.c.) induced an increase in 5-hydroxytryptamine (5-HT) synthesis in the spinal cord. These effects appeared with a shorter latency and are much more marked in the dorsal half than in the ventral half. Although the increase in the dorsal half was slightly delayed by comparison with the onset of the analgesic effect the maxima for both phenomena were simultaneous. The role of the bulbo-spinal serotonergic system in morphine analgesia is discussed.     

In vivo evidence for serotonin 5-HT2C receptor-mediated long-lasting excitability of lumbar spinal reflex and its functional interaction with 5-HT1A receptor in the mammalian spinal cord

The purpose of the present study was to investigate the 5-HT(2C) receptor-mediated effects on the spinal monosynaptic mass reflex activities and also its functional interactions with 5-HT(1A) receptors in anesthetized, acutely spinalized mammalian adult spinal cord in vivo. Intravenous administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) (0.1 mg/kg), an agonist of 5-HT(2A/2C) receptors, significantly increased the excitability of spinal motoneurons as reflected by an increase in the spinal monosynaptic mass reflex amplitude to 150-200% of the control. 5-HT(2A/2C) receptor-induced motoneuron excitability was slow, persistent and long-lasting for more than 2h that was significantly inhibited by 5-HT(2C) receptor specific antagonist SB 242084 administered 10 min prior to DOI. Simultaneous administration of DOI (0.1 mg/kg, i.v.) along with (+/-)-8-hydroxy dipropylaminotetraline hydrobromide (8-OH-DPAT) (0.1 mg/kg, i.v.) completely inhibited DOI-induced spinal monosynaptic mass reflex facilitation. In another separate study, administration of 8-OH-DPAT (0.1 mg/kg, i.v.) at the maximum response of DOI also inhibited the motoneuron's excitability; however, the inhibition lasted only for a period of 40-60 min after administration of 8-OH-DPAT, after which the spinal monosynaptic mass reflex amplitude reached its maximum level. These findings suggest that the 5-HT(2C) receptor is primarily involved in the mediation of the long-lasting excitability of spinal motoneurons and possibly interacts with its functional counterpart, 5-HT(1A) receptors in the mammalian adult spinal cord.     

Neuroanatomical site of the inhibitory influence of anxiolytic drugs on central serotonergic transmission

The neuroanatomical site of the inhibitory influence of anxiolytics on central serotonergic transmission has been investigated in the rat by studying the effect of systemic or intracerebral administration of these drugs on cerebral serotonin (5-HT) synthesis. Systemic administration of diazepam (3 mg/kg s.c.) or flunitrazepam (1 mg/kg, s.c.) caused a reduction of 5-HT synthesis (as measured by the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase) in the hippocampus but not in the cerebral cortex, striatum, cerebellum or spinal cord of the rat. Zopiclone (22 mg/kg, s.c.) decreased the amine synthesis in hippocampus, striatum and prefrontal cortex. The decrease of hippocampal 5-HT synthesis induced by diazepam (5 mg/kg, s.c.) was antagonized by the benzodiazepine antagonist Ro 15-1788 (2 X 30 mg/kg, s.c.) but not by bicuculline (2 X 1 mg/kg, s.c.). Acute cerebral hemitransection or electrolytic lesion of the fasciculus retroflexus did not prevent the ability of diazepam (5 mg/kg, i.p.) to diminish hippocampal 5-HT synthesis. Local infusion of diazepam (15 micrograms) of flurazepam (1.5 micrograms) into the hippocampus of conscious rats (via indwelling cannulae) markedly reduced 5-HT synthesis in this brain area whereas infusion of these drugs into the raphé medianus (origin of the serotonergic afferents to the hippocampus) failed to affect hippocampal 5-HT synthesis. In contrast, local injection of muscimol (25-150 ng) into the raphé medianus reduced 5-HT synthesis in the hippocampus. This effect of muscimol was potentiated by a systemic administration of diazepam or an intra-raphé medianus infusion of flurazepam (at doses or concentrations which exhibited no intrinsic activity). It is concluded from these data that anxiolytic drugs exert an inhibitory influence on hippocampal serotonergic neurons which is mediated primarily via GABA-independent benzodiazepine receptors located in the vicinity of serotonergic nerve terminals.     

Changes in brain and spinal tryptophan and 5-hydroxyindoleacetic acid levels following acute morphine administration in normal and arthritic rats.

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats. (1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord. (2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine. The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activation of the ascending pathway previously demonstrated by several authors and confirmed here.     

Morphine or U-50,488 suppresses Fos protein-like immunoreactivity in the spinal cord and nucleus tractus solitarii evoked by a noxious visceral stimulus in the rat.

Immunohistochemical visualization of Fos protein, the nuclear phosphoprotein product of the early-immediate gene c-fos, permits identification of populations of neurons that are activated in response to a variety of stimuli. This study examined the distribution of Fos-like immunoreactive (FLI) neurons in the spinal cord and the nucleus tractus solitarii (NTS) of the caudal medulla evoked by a noxious visceral stimulus in the unanesthetized rat. It also compared the inhibition of pain behavior and Fos expression by a mu-selective opioid agonist, morphine, and a kappa-selective opioid agonist, U-50,488. Intraperitoneal injection of 3.5% acetic acid in the unanesthetized rat evoked the expression of FLI in a discrete population of spinal cord neurons, the distribution of which closely mirrored the spinal terminations of visceral primary afferents. Specifically, FLI neurons were concentrated in laminae I, IIo, V, VII, and X. Large numbers of Fos-immunoreactive neurons were also present in the NTS of the caudal medulla, most likely as a result of spinosolitary tract and vaginal afferent input. The number of labeled neurons in both the spinal cord and the NTS was significantly correlated with the number of abdominal stretches, a pain behavior measure. Both morphine (1-10 mg/kg s.c.) and U-50,488 (3-30 mg/kg s.c.) produced a dose-dependent inhibition of the pain behavior in these animals and a dose-dependent suppression of the number of FLI neurons in both the spinal cord and in the NTS; complete suppression of FLI neurons was, however, not necessary for the production of antinociception. Furthermore, although equianalgesic doses of morphine and U-50,488 reduced the number of labelled neurons in the spinal cord to a comparable extent, morphine reduced the number of immunoreactive neurons in the NTS to a greater extent than did U-50,488. These results suggest that morphine and U-50,488 have comparable effects on the transmission of visceral nociceptive messages by spinal neurons, but differentially affect the autonomic response to noxious visceral stimuli.     

Pharmacological evidence for the involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC)

The involvement of serotonergic mechanisms in diffuse noxious inhibitory controls (DNIC) acting on dorsal horn convergent neurones has been studied in the anaesthetized rat. 35 neurones activated by transcutaneous electrical stimulation of their hindpaw receptive fields giving clear large A-fibre and C-fibre responses were recorded. These activities were conditioned by DNIC, evoked by either noxious heat applied to the tail or noxious pinch of the nose. Cinanserin (4 mg/kg i.v.) and metergoline (5 mg/kg i.v.), serotonin (5-HT) receptor blockers, strongly reduced the inhibitory effects of DNIC whilst having no significant effect on the non-conditioned responses. 5-Hydroxytryptophan, a precursor for 5-HT synthesis, significantly potentiated the effect of DNIC. These results indicate an important role for descending serotonergic pathways in DNIC. The functional role of this system is discussed.     

Changes in brain and spinal tryptophan and 5-hydroxy-indoleacetic acid levels follwing acute morphine administration in normal and arthritic rats

The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxy-tryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats.

(1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord.

(2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/ i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine.

The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activationn of theascending pathway previously demonstrated by several authors and confirmed here.     

Morphine microinjected into the nucleus raphe magnus does not block the activity of spinal trigeminal nucleus oralis convergent neurons in the rat

This study investigated the effects of morphine microinjection into the nucleus raphe magnus (RMg) on electrically evoked C-fiber activities of convergent neurons in the spinal trigeminal nucleus oralis (Sp5O), in halothane-anesthetized rats. Although the neurons could be depressed by systemic morphine (6 mg/kg, i.v.) in a naloxone-reversible fashion, morphine microinjected into the RMg (2.5 μg or 5 μg) neither depressed their C-fiber-evoked responses, nor the diffuse noxious inhibitory controls acting on them. It is concluded that the RMg is not involved in reinforcing descending inhibitory controls that are tonic or triggered by noxious stimuli acting on Sp5O convergent neurons.     

Effects of intrathecal BAM22 on noxious stimulus-evoked c-fos expression in the rat spinal dorsal horn

The effects of bovine adrenal medulla 22 (BAM22), a cleaved product of proenkephalin A, were investigated on the noxious stimulus-evoked expressions of spinal c-fos-like immunoreactivity (FLI). Heat (51 degrees C) applied to the tail evoked FLI predominantly in laminae I-II of the sacral spinal cord. Intrathecal (i.t.) BAM22 at a dose of 7 nmol decreased the expressions of the heat-evoked FLI by 68%, 64% and 56% in laminae I-II, III-IV and V-VI, respectively, and the decrease pattern was comparable to that induced by i.t. morphine (10 mug). Naloxone (1 mg/kg, i.p.) significantly enhanced the heat-evoked FLI in laminae III-VI, prevented the morphine-induced inhibition, and decreased the potencies of BAM22 in laminae I-II and V-VI by 23-40%. Higher dose of naloxone (10 mg/kg, i.p.) also partially reduced the BAM22-induced suppression. Following intraplantar injection of formalin (2.5%), FLI neurons were preferentially distributed not only in laminae I-II but also in laminae III-IV and V-VI of segments L4-L5. Pretreatment with BAM22 (7 nmol, i.t.) reduced the formalin-evoked FLI neurons by 72%, 61% and 58%, in laminae I-II, III-IV and V-VI, respectively. Naloxone (1 mg/kg. i.p.) enhanced the formalin-evoked expressions of FLI in laminae III-VI and decreased the potencies of BAM22 by 22-38% in laminae I-II and V-VI. The present study provided evidence at a cellular level showing that opioid and non-opioid effects of BAM22 on nociceptive processing in acute and persistent pain models were associated with modulation of noxious stimulus-evoked activity of the spinal dorsal horn neurons.     

The effect of fenfluramine on the thyrotropin-releasing hormone (TRH) content in the rat brain structures and lumbar spinal cord

The effect of fenfluramine (20 mg/kg i.p.) was studied on the thyrotropin-releasing hormone (TRH) content in several brain structures and the ventral part of the lumbar spinal cord of the rat. The effect of fenfluramine on the concentration of 5-hydroxytryptamine (5-HT) in some brain structures and the lumbar spinal cord was also examined. It was found that fenfluramine had no effect on the TRH level in the hypothalamus, hippocampus, occipital cortex, septum, nucleus accumbens and ventral part of the lumbar spinal cord, though the drug produced a profound depletion (by more than 60%) of 5-HT in the hypothalamus, nucleus accumbens, striatum and lumbar spinal cord. On the other hand, fenfluramine significantly increased the TRH content in the striatum, this effect was completely abolished by citalopram (20 mg/kg i.p.) or metergoline (10 mg/kg i.p.) Citalopram also prevented the fenfluramine-induced depletion of the striatal 5-HT. These results indicate a separate neuronal storage of TRH and 5-HT in the structures (ventral part of the lumbar spinal cord, nucleus accumbens, septum) in which the peptide and indoleamine coexist in 5-HT neurons. They also suggest that the fenfluramine-induced increase in the striatal TRH concentration is due to 5-HT release and stimulation of 5-HT receptors.     

Differential effects of spinal 5-HT1A receptor activation and 5-HT2A/2C receptor desensitization by chronic haloperidol

The effects of 7- and 21-day haloperidol treatment on the spinal serotonergic system were examined in vivo in acutely spinalized adult rats. Intravenous administration of a selective 5-HT(2A/2C) receptor agonist, (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (0.1 mg/kg) significantly increased the excitability of spinal motoneurones as reflected by increased monosynaptic mass reflex amplitude. This was significantly reduced in rats treated with haloperidol (1 mg/kg/day, i.p.) for 7 and 21 days. Administration of a 5-HT(1A/7) receptor agonist, (+/-)-8-Hydroxy dipropylaminotetraline hydrobromide (0.1 mg/kg, i.v.) significantly inhibited the monosynaptic mass reflex. This inhibition was greatly prolonged in haloperidol treated animals. These results demonstrate that the effects of haloperidol on the activation and desensitization of 5-HT(1A) and 5-HT(2A/2C) receptors respectively, may be mediated via intracellular mechanisms shared by these receptors with dopamine D(2) receptors in the mammalian spinal cord. The above serotonergic mechanisms may be partly responsible for haloperidol-induced extrapyramidal motor dysfunction.     

Differential effects of 5-HT1 and 5-HT2 receptor agonists on hindlimb movements in paraplegic mice

The effects induced by serotonergic (5-HT) agonists of the 5-HT1 and 5-HT2 subclasses were examined on hindlimb movement generation in adult mice completely spinal cord transected at the low thoracic level. One week postspinalization, intraperitoneal injection (0.5-10 mg/kg) of meta-chlorophenylpiperazine (m-CPP; 5-HT(2B/2C) agonist) or trifluoromethylpiperazine (TFMPP; 5-HT(1B) agonist) failed to induce locomotor-like movements. However, dose-dependent nonlocomotor movements were induced in air-stepping condition or on a motor-driven treadmill. In contrast, hindlimb locomotor-like movements were found after the injection of quipazine (5-HT(2A/2C) agonist; 1-2 mg/kg). Combined with L-DOPA (50 mg/kg, i.p.), low doses of quipazine but not of m-CPP and TFMPP produced locomotor-like and nonlocomotor movements in air-stepping condition or on the treadmill. Subsequent administration of m-CPP or TFMPP significantly reduced and often completely abolished the hindlimb movements induced by quipazine and L-DOPA. Altogether, these results demonstrate that 5-HT(2A/2C) receptor agonists promote locomotion while 5-HT(1B) and 5-HT(2B/2C) receptor agonists interfere with locomotor genesis in the hindlimbs of complete paraplegic mice. These results suggest that only subsets of spinal 5-HT receptors are specific to locomotor rhythmogenesis and should be activated to successfully induce stepping movements after spinal cord injury.     

Effect of subcutaneous administration of the chemical algogen formalin, on 5-HT metabolism in the nucleus raphe magnus and the medullary dorsal horn: a voltammetric study in freely moving rats

The effect of subcutaneous administration of the chemical algogen formalin, on serotonin (5-HT) metabolism in the nucleus raphe magnus (NRM) and the medullary dorsal horn (MDH) has been investigated using in vivo 5-hydroxyindole electrochemical (peak ‘3’) detection with treated, multi-carbon fiber electrodes and differential pulse, or normal pulse, voltammetry in freely moving rats. The subcutaneous (s.c.) injection of 50 μl of 10% formalin in the left forepaw was followed, at the NRM level, by a significant increase in the voltammograms as compared to controls (50 μl of saline 0.9% s.c. in left forepaw) for about 70 min after the injection, before a return to control values. At the MDH level, the formalin injection induced no significant effect on peak 3, as compared to controls, during the first 70 min. After that, the voltammograms significantly increased and remained above controls for up to 180 min. Thus, the time-courses of NRM and MDH effects appear markedly different. These findings suggest that, depending on the anatomical level (NRM or MDH) and/or the period of observation, one can measure differences in the time-course of the increase in 5-HT metabolism in the NRM-dorsal horn serotonergic system by tonic noxious stimuli, such as the formalin test.     

The medullary dorsal horn: a target for the expression of opiate effects on the perceived intensity of noxious heat

We examined the effects of morphine microinjected into the medullary dorsal horn (MDH) on the ability of monkeys to detect temperature increases in the noxious heat range. Behavioral detection latency and the percentage of correct detections were used as measures of the perceived intensity of noxious heat stimuli. Three monkeys were trained to detect a change (T2) of 0.4, 0.6, or 1.0 degrees C from a previous noxious heat level of 46 degrees C (T1). Effects on attentional, motivational, and motoric aspects of the monkeys' behavior were assessed by having them detect innocuous cooling and visual stimuli in tasks of similar difficulty. Morphine (1, 3, and 10 micrograms) microinjected into the MDH produced a dose-dependent and stimulus-intensity-dependent increase in the latency to detection of the T2 stimuli. These effects were opiate receptor-mediated since they were antagonized by systemically administered naloxone (0.5 mg/kg, i.m.) given 40 min after the microinjection of morphine. There were no effects of morphine on the behavioral detection latencies to the innocuous cooling and visual stimuli, indicating that the effects of morphine were modality-specific and independent of changes in motivation, attention, or motoric ability. These data demonstrate a pharmacologically specific effect of opiates on the perceived intensity of noxious heat stimuli at the earliest central relay pathway transmitting noxious information.     

The effect of morphine on responses of nucleus ventroposterolateralis neurons to colorectal distension in the rat

In 71 halothane-anesthetized rats, we characterized the responses of single neurons in the nucleus ventroposterolateralis (VPL) of the thalamus to a noxious visceral stimulus (colorectal balloon distension; CRD) and studied the effects of intravenous morphine on these responses using standard extracellular microelectrode recording techniques. One hundred nine neurons were isolated on the basis of spontaneous activity. Sixty-four (59%) responded to CRD, of which 52 (81 %) had excitatory and 12 (19%) had inhibitory responses. Neurons showed graded responses to graded CRD pressures (20-100 mmHg), with maximum excitation or inhibition occurring at 80 mmHg. Responses to noxious (pinch, heat) and innocuous (brush, tap) cutaneous stimuli were studied in 95 of the VPL neurons isolated. Eighty-three of these neurons (48 CRD responsive and 35 CRD nonresponsive) (87%) had cutaneous receptive fields, of which 96% were small and contralateral and 4% were large and contralateral or bilateral. Ninety-four percent of these neurons responded to both noxious and innocuous cutaneous stimulation, and 6% responded to only noxious stimulation. No neurons responded solely to innocuous stimulation. Cumulative doses of morphine (0.125, 0.25, 0.5, 1, and 2 mg/kg, i.v) produced statistically significant dose-dependent attenuation of neuronal responses to CRD. Naloxone (0.4 mg/ kg, i.v.) reversed the effects of morphine. Morphine and naloxone had no significant effects on spontaneous activity. These data support the involvement of VPL neurons in visceral nociception and are consistent with a role of VPL in sensory-discriminative aspects of nociception.