Analgesia,development of tolerance,and 5-hydroxytryptamine turnover in the rat after cerebral and systemic administration of morphine

Morphine HCl (10 μ/0.5 μl) was injected into the right striatum, the caudal aqueduct and the region of the nucleus raphe magnus of the rat. Turnover of 5-hyrdroxytryptamine (5-HT) in the brain was assessed by fluorimetric estimation of 5-hydroxyindol-3-ylacetic acid following the administration of probenecid. Injection into the right striatum (a region containing 5-HT terminals) increased 5-HT turnover in the right, but not in the left striatum or in the anterior medulla. The pain threshold was unaltered. Injection into the aqueduct accelerated 5-HT turnover in the anterior medulla, but the striata and spinal cord showed no such change. Analgesia was pronounced. Injection of morphine into the region of the nucleus raphe magnus caused analgesia and increased 5-HT turnover in the posterior medulla and the spinal cord. The action on the cord must have been the result of the stimulation of cells in the raphe. The effects of the local injections of morphine on 5-HT turnover were antagonized by systemic naloxone (1–2mg/kg) in all the regions studied.When morphine was administered subcutaneously three times a day for five days, tolerance developed to the analgesic effect of morphine (7mg/kg). However, tolerance to its acceleration of 5-HT turnover was only seen in the spinal cord, not in striatum or anterior and posterior medulla. When morphine was withdrawn, its effects on analgesia and 5-HT turnover in the spinal cord recovered simultaneously.The results emphasize the likely part played by the descending serotoninergic pathway in the analgesic effect of morphine.     

Electrolytic raphe magnus lesions block analgesia induced by a stress-morphine interaction but not analgesia induced by morphine alone

Morphine analgesia in the tail withdrawal test was examined in rats which had had lesions of the nucleus raphe magnus (NRM) or sham operations. Half of the rats were tested while restrained, whereas the other half were not restrained. In the sham-operated rats, restraint potentiated the analgesic response to morphine. Lesions of the NRM had no effect on unrestrained rats but reduced the morphine analgesia exhibited by restrained rats so that it was indistinguishable from that of unrestrained rats. The NRM seems to be involved in analgesia induced by an interaction of morphine and restraint but not in analgesia induced by morphine alone.     

Long-lasting delayed hyperalgesia after chronic restraint stress in rats-effect of morphine administration

Different effects upon the nociceptive response have been observed with exposure to acute and chronic stress in rats. In the present study we repeatedly submitted rats to restraint for 40 days, inducing hyperalgesia using the tail-flick test. A new session of acute stress was applied at the end of 40 days period, and the chronically-stressed animals demonstrated analgesia after forced swimming, but not after restraint. The effect of stress interruption for 14 or 28 days on the nociceptive threshold was then investigated. The basal tail-flick latency remained decreased for at least 28 days (hyperalgesic effect). Following the periods of suspension, the animals were submitted to new session of acute restraint, and stress-induced analgesia was observed only after 28 days of stress interruption. Thus, the mechanisms involved in the long-lasting hyperalgesia presented in this study are not exactly the same as those responsible for the analgesia induced by acute stressors. After 40 days of chronic stress treatment, morphine was injected i.p. (1.0, 5.0 mg/kg or saline). The repeatedly stressed rats displayed decreased morphine effects on nociception compared to unstressed controls. The tolerance of the response to morphine agrees with previous studies suggesting that chronic restraint stress could modify the activity of opioid systems.     

Inescapable shock-induced potentiation of morphine analgesia in rats: sites of action.

Inescapable shock (IS) enhances analgesia to systemic morphine (MOR) 24 hr later. IS activates serotonin neurons in the dorsal raphe nucleus (DRN), rendering them hyperexcitable. These studies tested whether IS potentiates the analgesic effect of MOR microinjected in the DRN, as predicted by this hypothesis. To test site specificity, the effect of previous IS was examined on MOR microinjected lateral to the DRN and into 2 other sites that support MOR analgesia, the nucleus raphe magnus (NRM) and spinal cord. Twenty-four hours after IS, potentiated analgesia was observed after 0.5 microg MOR microinjected into, but not lateral to, the DRN. Potentiated analgesia was also observed after NRM (1.0 microg) and spinal cord (3.0 microg) MOR microinjections. These data suggest that IS-induced excitability changes within the DRN synergize with opiates microinjected in other analgesia areas and that this potentiates the responses to opiates 24 hr after IS.     

Inhibition of mesencephalic morphine analgesia by methysergide in the medial ventral medulla of rats.

The neural substrates of endogenous supraspinal opioid pain inhibition are mediated in part by connections between the midbrain periaqueductal gray (PAG) and the ventral-medial medulla, including the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis (NRGC). To ascertain whether a serotonergic synapse participated in this pathway, the present study determined whether microinjections of methysergide into the NRM or NRGC would alter analgesia elicited by morphine microinjections into the PAG. Morphine (2.5 micrograms) in the PAG and immediately adjacent areas produced significant analgesia on the tail-flick and jump tests in rats. Pretreatment with the serotonin receptor antagonist methysergide (0.5-5 micrograms) in either the NRM or NRGC significantly reduced morphine analgesia elicited from the PAG by 69% on the tail-flick and by 50% on the jump tests without altering basal nociceptive thresholds. Medullary placements ventral or lateral to the NRM/NRGC failed to support this antagonistic effect. These data indicate that a ventro-medial medullary serotonergic synapse participates in the transmission of opioid pain-inhibitory signals from the PAG.     

Collateralization of periaqueductal gray neurons to forebrain or diencephalon and to the medullary nucleus raphe magnus in the rat.

Antinociceptive effects elicited from the midbrain may involve both ascending and descending projections from the periaqueductal gray and dorsal raphe nucleus. To investigate the relationship between these different efferent pathways in the rat, we performed a double-labeling study using two retrograde tracers, colloidal gold-coupled wheatgerm agglutinin-apo horseradish peroxidase and a fluorescent dye. One tracer was microinjected in the medullary nucleus raphe magnus; the second was injected into one of several regions rostral to the periaqueductal gray that have been implicated in nociceptive and antinociceptive processes. The results can be grouped into two categories. First, injections into the ventrobasal thalamus, lateral hypothalamus, amygdala, and cerebral cortex labeled neurons in the dorsal raphe nucleus but not in the periaqueductal gray. Up to 90% of these projection neurons were serotonin immunoreactive, and up to 17% were also retrogradely labeled from the nucleus raphe magnus. Second, only injections into the ventrobasal hypothalamus (which included the beta-endorphin-containing arcuate neurons) or into the medial thalamus labeled neurons in the periaqueductal gray itself. Injections into the medial thalamus, but not into the ventrobasal hypothalamus, also labeled neurons in the dorsal raphe nucleus. Up to 20% of the neurons retrogradely labeled from these regions were also retrogradely labeled from nucleus raphe magnus. The presence of large populations of rostrally projecting periaqueductal gray neurons that collateralize to the nucleus raphe magnus implies that activity in ascending projections necessarily accompanies any activation of the periaqueductal gray-nucleus raphe magnus pathway. Possibly, projections from the medial thalamus and medial hypothalamus mediate antinociceptive effects that complement descending inhibition. Finally, possible antidromic activation of these pathways must be considered when interpreting the results of electrical brain stimulation studies.     

The nuclei of origin of brain stem enkephalin and substance P projections to the rodent nucleus raphe magnus

The sites of origin of brain stem enkephalin and substance P projections to the rodent nucleus raphe magnus were studied utilizing the combined horseradish peroxidase retrograde transport-peroxidase-antiperoxidase immunohistochemical technique. Several brain stem areas were found to contain both enkephalin- and substance P-like immunoreactive double labeled neurons following injection of horseradish peroxidase into the raphe magnus. Nuclei providing both enkephalin and substance P inputs to the raphe magnus include the nucleus reticularis paragigantocellularis, the nucleus cuneiformis, the nucleus solitarius and the trigeminal subdivision of the lateral reticular nucleus. Enkephalin projections to the raphe magnus were also found to originate from the dorsal parabrachial nucleus, the nucleus reticularis gigantocellularis pars α and from an area which corresponds to the A5 group of Dahlström &; Fuxe. Additional neurons containing substance P-like immunoreactivity and horseradish peroxidase reaction product were identified in the superior central raphe nucleus and the nucleus pontis oralis. The midbrain periaqueductal gray contributes very few enkephalin and substance P fibers to the raphe magnus.The nucleus raphe magnus is a key structure in the intrinsic analgesia system and it has also been implicated in other diverse and non-nonciceptive functions. The present study identifies several brain stem sites which provide enkephalin and substance P input to this raphe nucleus. Several of these nuclei have been implicated in central analgesic mechanisms or in non-nociceptive autonomic functions. The present investigation raises the possibility that these brain stem regions may modulate neuronal activity in the raphe magnus via enkephalin or substance P projections and thus influence the involvement of the raphe magnus in both opiate related mechanisms of pain control and non-nociceptive functions.     

Differential actions of the blockade of spinal opioid, adrenergic and serotonergic receptors on the tail-flick inhibition induced by morphine microinjected into dorsal raphe and central gray in rats

Microinjection of morphine sulfate into dorsal raphe, ventrolateral central gray and dorsolateral central gray inhibits spinal nociceptive reflexes. The effects of the blockade of spinal opioid, adrenergic, and serotonergic receptors by intrathecal injection of naloxone, yohimbine and methysergide, respectively, on inhibition of the tail-flick response induced by morphine microinjected into dorsal raphe, ventrolateral central gray and dorsolateral central gray were studied. Naloxone (20 micrograms) given intrathecally effectively antagonized inhibition of the tail-flick response induced by morphine (4 micrograms) given into dorsal raphe and ventrolateral central gray, but not dorsolateral central gray. On the other hand, intrathecal injection of yohimbine (30 micrograms) antagonized inhibition of the tail-flick response induced by morphine given into ventrolateral central gray and dorsolateral central gray, but not dorsal raphe. Intrathecal injection of prazosin (30 micrograms) did not antagonize inhibition of the tail-flick response induced by morphine given into dorsal raphe or lateral central gray. Intrathecal injection of methysergide (30 micrograms) only partially antagonized inhibition of the tail-flick response induced by morphine given into dorsal raphe, but not ventrolateral central gray and dorsolateral central gray. It is concluded that the analgesia induced by morphine injected into dorsal raphe is mediated by spinal opioid receptors but not by spinal alpha 2-adrenergic receptors while the analgesia produced by morphine given into dorsolateral central gray is mediated by spinal alpha 2-adrenergic receptors. The analgesia induced by morphine given into ventrolateral central gray is mediated in part by both spinal alpha 2-adrenergic and opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

A fluorescence histochemical and biochemical evaluation of the effect of p-chloroamphetamine on individual serotonergic nuclei in the rat brain.

The serotonin (5-hydroxytryptamine) content of eight raphe nuclei was measured 9 days after injection of p-chloroamphetamine. 5-Hydroxytryptamine levels were reduced in only the B-9 cell group.The histofluorescence of serotonergic neurons in the B-9 cell group was also studied at two time intervals after a single injection of p-chloroamphetamine. Nine days after the administration of p-chloroamphetamine there was a small decrease both in the intensity of fluorescence and in the number of yellow fluorescent serotonergic cells. After 2 months the drug caused a more marked decrease in the number of viable serotonergic cells. The results are discussed in relation to the mechanism of action of p-chloroamphetamine.It is suggested that following the administration of p-chloroamphetamine retrograde destruction may occur in the B-9 cell group, in contrast to those of the other raphe nuclei, whose cell bodies may possess a sufficient number of collateral processes to resist the slow neurotoxic destruction of their cell bodies.     

Tooth pulp stimulation advances both medullary off-cell pause and tail flick

It has been postulated that the so-called off-cells of nucleus raphe magnus and adjacent structures in the rat are the output elements of a system which inhibits nociceptive transmission at the spinal cord. Off-cells stop firing about 0.4 s before the tail flick reflex (TF) elicited by the application of noxious heat to the tail. When continuous off-cell activity is induced by either morphine injection or periaqueductal gray stimulation, the TF is delayed. The present results show that electrical stimulation of the tooth pulp (TP) causes the off-cells to stop firing. Furthermore, when TP is stimulated during tail heating and before the expected time for TF, off-cells stop firing earlier and the TF occurs also earlier. This supports the notion that off-cells inhibit nociceptive transmission.     

Intraventricular capsaicin: alterations in analgesic responsivity without depletion of substance P

Both systemic and intrathecal capsaicin release and deplete substance P from primary sensory afferents and induce prolonged chemical and thermal analgesia. Given the existence of efferents containing substance P together with a pain-inhibitory serotoninergic pathway, the present study investigated the effects of intraventricular capsaicin upon basal nociception, analgesic responsivity to opiates and substance P immunoreactivity. Following treatment with capsaicin at doses of 25, 50 and 100 micrograms or with vehicle, alterations in basal rodent flinch-jump thresholds as well as analgesic responses to 5 and 2.5 mg/kg of morphine were measured over a post-injection time course. Tissues were then processed for immunocytochemistry for substance P according to the unlabelled antibody peroxidase antiperoxidase procedure. Decreases were noted in jump thresholds only at 72 h following capsaicin. Moreover, morphine analgesia at both doses was attenuated in dose-dependent fashion following capsaicin with the highest dose (100 micrograms) producing a significant decrease in analgesic efficacy. Substance P-like immunoreactivity in capsaicin-treated rats was not appreciably depleted compared with vehicle controls in the substantia gelatinosa of the spinal cord and V cranial nerve, the raphe magnus and periaqueductal gray, the medullary, pontine and mesencephalic reticular formation, the substantia nigra, the corpus striatum and the central nucleus of the amygdala. By contrast, substance P-like immunoreactivity appeared to increase in the medial nucleus of the amygdala. In the absence of depletion of substance P immunoreactivity by the intraventricular capsaicin, the observed alterations in opiate analgesic responses may possibly be due to alterations in other transmitters or peptide systems.     

The raphe magnus/pallidus regulates sweat secretion and skin vasodilation of the cat forepaw pad: a preliminary electrical stimulation study

In the human palm/sole, mental or physical stimuli induce an increase in sweat secretion and a decrease in skin blood flow (SkBF). However, the central pathways of these responses remain unclear. We measured sweat secretion and SkBF in the cat footpad by electrically stimulating the raphe. Stimulation of the rostral raphe magnus/pallidus elicited a reduction in SkBF without affecting sweat secretion. Stimulation of the mid to caudal raphe magnus/pallidus elicited an increase in both sweat secretion and SkBF. The raphe magnus/pallidus may play a crucial role in skin vasomotor and sudomotor responses in the cat footpad.     

大鼠脑干5-羟色胺能和儿茶酚胺能神经元向孤束核的投射——荧光金标记结合免疫荧光技术研究

应用荧光金逆行追踪和免疫荧光技术相结合的方法,对投射至大鼠孤束核的５－羟色胺能和儿茶酚胺能神经纤维的脑干来源进行了研究。结果证明,将荧光金注入一侧孤束核的中尾段,逆标神经元分布于脑干下行抑制系统的大部分核团。结合５－羟色胺和酪氨酸羟化酶免疫荧光组织化学技术研究发现：荧光金／５－ＨＴ 双重反应阳性神经元分布于中脑导水管周围灰质的腹外侧区、中缝背核、脑桥被盖网状核、脑桥尾侧网状核、中缝桥核、中缝正中核、中缝大核、巨细胞网状核α部、中缝隐核和中缝苍白核等核团,其中中央灰质腹外侧区、中缝大核、巨细胞网状核α部、中缝隐核、中缝苍白核等处的荧光金／５－ＨＴ 双重反应阳性神经元数量占脑干向孤束核投射的５－ＨＴ 阳性神经元总数的近７０％ （６９．９１％ ）;荧光金／酪氨酸羟化酶双重反应阳性神经元主要分布于脑干中脑中央灰质腹外侧区、Ａ７、蓝斑及蓝斑下核（Ａ６）、Ａ５、巨细胞网状核α部和Ａ１ 等核团,其中中央灰质腹外侧区、Ａ５、巨细胞网状核α部和Ａ１ 内的荧光金／酪氨酸羟化酶神经元数量占脑干向孤束核投射的酪氨酸羟化酶阳性神经元总数的８８．１７％ 。本研究提示,大鼠脑干下行抑制系统形成了至ＮＴＳ中尾段的以中脑中央灰质腹外侧区及中缝大核、?     

Raphe magnus inhibition of feline T1-T4 spinoreticular tract cell responses to visceral and somatic inputs

Background activity of spinoreticular tract neurons in the T1-T4 segments was on average inhibited 80% by electrical stimulation of nucleus raphe magnus. Nucleus raphe magnus stimulation inhibited responses of spinoreticular tract neurons to somatic input produced by touching the skin and hair (innocuous stimulus) or pinching the skin and muscle (noxious stimulus). Inhibition of responses to noxious and innocuous somatic inputs was not significantly different. Inhibition produced during nucleus raphe magnus stimulation was less effective when the activity of spinoreticular tract cells increased. This relationship was consistent for both background activity and responses to somatic noxious or innocuous input. Nucleus raphe magnus stimulation inhibited responses of spinoreticular tract neurons to visceral input produced by electrical stimulation of cardiopulmonary sympathetic afferent fibers. Responses to C-fiber sympathetic afferent fibers were more effectively inhibited than were responses to A-delta sympathetic afferent fibers. In conclusion, stimulation of the nucleus raphe magnus inhibits T1-T4 spinoreticular tract neuronal responses to visceral and somatic inputs. Since spinoreticular neurons project to the medullary reticular formation, activation of the nucleus raphe magnus could modulate affective-motivational behavior and cardiovascular adjustments that often occur during angina pectoris.     

Potential role of medullary raphe-spinal neurons in cutaneous vasoconstriction: an in vivo electrophysiological study

In rabbits, raphe magnus/pallidus neurons form a link in the CNS pathway regulating changes in cutaneous blood flow elicited by nociceptive stimulation and activation of the central nucleus of the amygdala. To characterize relevant raphe-spinal neurons, we performed extracellular recordings from the rostral medullary raphe nuclei in anesthetized, paralyzed, mechanically ventilated rabbits. All studied neurons were antidromically activated from the dorsolateral funiculus of the spinal cord (C(8)-T(2)). Of 129 studied neurons, 40% were silent. The remaining neurons discharged spontaneously at 0.3-29 Hz. Nociceptive stimulation (lip squeeze with pliers) excited 63 (49%), inhibited 9 (7%), and did not affect 57 (44%) neurons. The same stimulation also elicited falls in ear pinna blood flow. In neurons activated by the stimulation, the increase in discharge preceded the fall in flow. Electrical stimulation of the spinal trigeminal tract excited 61/63 nociception-activated neurons [onset latencies range: 6-75 ms, mean: 28 +/- 3 (SE) ms], inhibited 9/9 nociception-inhibited neurons (onset latencies range: 9-85 ms, mean: 32 +/- 10 ms), and failed to affect 55/57 neurons insensitive to nociceptive stimulation. Neurons insensitive to nociceptive/trigeminal stimulation were also insensitive to nonnociceptive tactile stimulation and to electrical stimulation of the amygdala. They were either silent (32/45) or discharged regularly at low frequencies. They possessed long-duration action potentials (1.26 +/- 0.08 ms) and slow-conducting axons (6.0 +/- 0.5 m/s). These neurons may be serotonergic raphe-spinal cells. They do not appear to be involved in nociceptive-related cutaneous vascular control. Of the 63 neurons sensitive to nociceptive and trigeminal tract stimulation, 35 also responded to tactile stimulation (wide receptive field). These neurons possessed short action potentials (0.80 +/- 0.03 ms) and fast-conducting axons (30.3 +/- 3.1 m/s). In this subpopulation, electrical stimulation of the amygdala activated nearly all neurons tested (10/12), with a mean onset latency of 34 +/- 3 ms. The remaining 28 neurons sensitive to nociceptive and trigeminal stimulation did not respond to tactile stimuli and were mainly unaffected by amygdala stimulation. It may be that fast-conducting raphe-spinal neurons, with wide multimodal receptive fields and with input from the central nucleus of the amygdala, constitute the bulbo-spinal link in the CNS pathway regulating cutaneous blood flow in response to nociceptive and alerting stimuli.     

Anxiolytic-like behavior after lesion of the tuberomammillary nucleus E2-region

The tuberomammillary nucleus (TM), located in the posterior hypothalamic region, consists of five subgroups and is the only known source of brain histamine. In the present experiment, rats received bilateral ibotenic acid or sham lesions in the rostroventral part of the TM (E2-region). Three weeks later they were tested on the elevated plus-maze test of fear and anxiety. Lesions in the tuberomammillary E2-region elevated the time spent on the open arms, as well as excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. Thus, partial destruction of TM intrinsic neurons can induce anxiolytic-like effects which are possibly related to a lesion-induced reduction of histaminergic activity. Received: 28 August 1997 / Accepted: 20 November 1997     

A brainstem substrate for analgesia elicited by intraoral sucrose

Previous studies demonstrated that nursing or intraoral infusion of certain components of mother's milk (e.g. sugars and fats) produces calming and opiate receptor-dependent analgesia in newborn rats and humans. However, the neural circuitry underlying such analgesia is unknown. The aim of the present study was to specify the central pathways by which taste stimuli engage neural antinociceptive mechanisms. For this purpose, midcollicular transactions were used to investigate the role of the forebrain in analgesia elicited by intraoral infusion of 0.2 M sucrose in neonatal rats. Sucrose-induced analgesia persisted, and was enhanced, following midcollicular transection, indicating that it did not require neural circuits confined to the forebrain. Fos immunohistochemistry was used to identify brainstem neurons activated by a brief (90 s) intraoral infusion of a small volume (90 microl, 0.2M) of sucrose or a salt solution (0.1 M ammonium chloride) in 10-day-old rat pups. Compared with control groups (intact, cannula, distilled water), both sucrose and ammonium chloride induced Fos expression in the rostral nucleus tractus solitarius, the first relay in the ascending gustatory pathway. Sucrose also elicited Fos expression in several brainstem areas associated with centrally mediated analgesia, including the periaqueductal gray and the nucleus raphe magnus. Taken together, these findings demonstrate that analgesia elicited by intraoral sucrose does not require involvement of the forebrain. Intraoral sucrose activates neurons in the periaqueductal gray and nucleus raphe magnus, two key brainstem sites critically involved in descending pain modulation.     

Hypothalamic control of nocireceptive and other neurones in the marginal layer of the dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat

Summary The effect of electrical stimulation of the preoptic area of the hypothalamus on the discharge of neurones in the marginal layer (lamina I) of the trigeminal nucleus caudalis was studied in the anaesthetised rat. There was a powerful suppression of the discharge evoked by noxious thermal stimuli in 49/49 specific nociceptor driven (nocireceptive) neurones. The inhibitory effect increased with graded increases in the intensity of preoptic stimulation. Stimulation, however, produced only a small reduction in the discharge of 14/17 cold receptive neurones. Thresholds for producing suppression of cold receptive neurones were generally higher than those for nocireceptive neurones. There was no effect on the activity of 12/12 low threshold mechanoreceptive neurones. The inhibitory action generated on the activity of nocireceptive neurones was reduced by electrolytic lesions in the nucleus raphe magnus (NRM) or the nucleus paragigantocellularis lateralis (PGCL) or the dorsolateral and ventrolateral periaqueductal gray matter (PAG). Lesions made in the ventral or dorsal aspect of PAG were, however, ineffective in reducing the suppression. It is suggested that the powerful descending inhibitory control of nociceptive transmission in the trigeminal nucleus caudalis is one of the neuronal mechanisms mediating analgesia from the preoptic area of the hypothalamus.     

Decreased opioid analgesia in weanling rats exposed to endothelin-1 during infancy

Endothelin-1 produces spontaneous nociceptive-associated behaviors that are modulated by the peripheral opioid system. The present study tests the hypothesis that single or repeated exposure to endothelin-1 during infancy decreases opioid analgesia in weanling rats. Morphine analgesia was measured in male and female postnatal day 21 rats following intraplantar endothelin-1 on postnatal day 7, or 11 or both days 7 and 11. In males, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC₅₀ = 0.902 and 1.326 mg/kg, respectively) compared to control (EC₅₀ = 0.486 mg/kg). Similarly in females, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC₅₀ = 1.367 and 1.226 mg/kg, respectively) compared to control (EC₅₀ = 0.468 mg/kg). In addition, females exposed to endothelin-1 on postnatal day 7 exhibited an intermediate decrease in morphine analgesia with an EC₅₀ of 0.752 mg/kg. In males, exposure to endothelin-1 decreased mu opioid receptor expression without changing endothelin-A receptor or endothelin-B receptor expression in the hindpaw skin. In contrast, in females, exposure to endothelin-1 increased expression of both endothelin receptors and the mu opioid receptor in hindpaw skin. These findings suggest a sex-difference in the window of vulnerability and the mechanism by which an acute nociceptive event can induce morphine tolerance.     

大鼠丘脑束旁核和外侧缰核向中脑导水管周围灰质和中缝大核的分枝投射──荧光素双标记法研究

将ＦａｓｔＢｌｕｅ（ＦＢ）和ＤｉａｍｉｄｉｎｏＹｅｌｌｏｗ（ＤＹ）分别定向注入中脑导水管周围灰质和中缝大核，在丘脑束旁核和外侧缰核内侧部见到ＦＢ单标、ＤＹ单标及ＦＢ／ＤＹ双标神经元．在丘脑束旁核，双标神经元占该核三种标记神经元总数的１３．１％；在外侧缰核内侧部，双标神经元占三种标记神经元总数的１８．６％．双标记神经元呈梭形、三角形和椭圆形，胞体的直径约为１５～３０μｍ．