Mu opioid receptor expressing neurons in the rostral ventromedial medulla are the source of mechanical hypersensitivity induced by repeated restraint stress.

Repeated exposure to psychophysical stress often causes an increase in sensitivity and response to pain. This phenomenon is commonly called stress-induced hyperalgesia (SIH). Although psychophysical stress is a well-known risk factor for numerous chronic pain syndromes, the neural mechanism underlying SIH has not yet been elucidated. The rostral ventromedial medulla (RVM) is a key output element of the descending pain modulation system. Descending signals from the RVM have a major impact on spinal nociceptive neurotransmission. In the present study, to clarify changes in the descending pain modulatory system in rats with SIH, we examined the expression of Mu opioid receptor (MOR) mRNA, MeCP2 and global DNA methylation in the RVM after repeated restraint stress for 3 weeks. Additionally, we microinjected neurotoxin dermorphin-SAP into the RVM. The repeated restraint stress for 3 weeks induced mechanical hypersensitivity in the hind paw, a significant increase in the expression of MOR mRNA and MeCP2, and a significant decrease in global DNA methylation in the RVM. The MeCP2 binding to MOR gene promoter in the RVM was significantly decreased in rats with repeated restraint stress. Furthermore, microinjection of dermorphin-SAP into the RVM prevented the mechanical hypersensitivity induced by repeated restraint stress. Although, because of the lack of specific antibody to MOR, we could not show a quantitative analysis in the number of MOR-expressing neurons after the microinjection, these results suggest that MOR-expressing neurons in the RVM induce SIH after repeated restraint stress.

Significance of medial preoptic area among the subcortical and cortical areas that are related to pain regulation in the rats with stress-induced hyperalgesia.

Psychophysical stresses frequently increase sensitivity and response to pain, which is termed stress-induced hyperalgesia (SIH). However, the mechanism remains unknown. The subcortical areas such as medial preoptic area (MPO), dorsomedial nucleus of the hypothalamus (DMH), basolateral (BLA) and central nuclei of the amygdala (CeA), and the cortical areas such as insular (IC) and anterior cingulate cortices (ACC) play an important role in pain control via the descending pain modulatory system. In the present study we examined the expression of phosphorylated -cAMP-response element binding protein (pCREB) and the acetylation of histone H3 in these subcortical and cortical areas after repeated restraint stress to reveal changes in the subcortical and cortical areas that affect the function of descending pain modulatory system in the rats with SIH. The repeated restraint stress for 3 weeks induced a decrease in mechanical threshold in the rat hindpaw, an increase in the expression of pCREB in the MPO and an increase in the acetylation of histone H3 in the MPO, BLA and IC. The MPO was the only area that showed an increase in both the expression of pCREB and the acetylation of histone H3 among these examined areas after the repeated restraint stress. Furthermore, the number of pCREB-IR or acetylated histone H3-IR cells in the MPO was negatively correlated with the mechanical threshold. Together, our data represent the importance of the MPO among the subcortical and cortical areas that control descending pain modulatory system under the condition of SIH.

Modulatory effects of repeated psychophysical stress on masseter muscle nociception in the nucleus raphe magnus of rats.

Psychophysical stress can cause neural changes that increase nociception in the orofacial region, particularly the masseter muscle (MM). The nucleus raphe magnus (NRM), which is located in the brain stem, serves the crucial role of regulating nociception through descending modulatory pain control. However, it remains unclear if neural activities in the NRM are affected under psychophysical stress conditions. This study conducted experiments to assess (1) whether neural activity, indicated by Fos expression in an NRM that has experienced MM injury, is affected by the stress of repeated forced swim tests (FST); and (2) whether the selective serotonin reuptake inhibitor fluoxetine administered daily after an FST could affect the number of Fos-positive neurons in the NRM. Results revealed that the stress from repeated FSTs significantly increased the number of Fos-positive neurons in an NRM that had been affected by MM injury. Fluoxetine inhibited increases in the number of Fos-positive neurons in the NRM that occurred as a result of FSTs, but this was not observed in sham rats. These findings indicate that the stress from FSTs could increase nociceptive neural activity in an NRM that has experienced MM injury. This could be due, in part, to changes in serotonergic mechanisms.

Increase of histone acetylation in the GABAergic neurons in the rostral ventromedial medulla associated with mechanical hypersensitivity after repeated restraint stress.

Psychophysical stresses frequently increase sensitivity and response to pain, which is termed stress-induced hyperalgesia (SIH). However, the mechanism remains unknown. The rostral ventromedial medulla (RVM) and locus coeruleus (LC) are core elements of the descending pain modulatory system, which modulate nociceptive transmission in the spinal dorsal horn. In the present study we examined the acetylation of histone H3 in the RVM and LC after repeated restraint stress for 3 weeks to clarify changes in the descending pain modulatory system in the rat with SIH. The repeated restraint stress induced mechanical hypersensitivity in the hindpaw and an increase in acetylation of histone H3 in the RVM but not the LC. The number of acetylated histone H3-IR cells in the RVM was significantly higher in the repeated restraint group (282.9 ± 43.1) than that in the control group (134.7 ± 15.6, p < 0.05). Furthermore, the repeated restraint stress increased acetylation of histone H3 in the RVM GABAergic neurons but not the RVM serotonergic neurons. The GAD67 protein level in the RVM was significantly higher in repeated restraint group (144.9 ± 17.0%) than that in the control group (100.0 ± 8.9%, p < 0.05). These findings suggest the possibility that the stress-induced neuroplasticity in the RVM GABAergic neurons is involved in the mechanical hypersensitivity due to the dysfunction of the descending pain modulatory system.

Robust Subthreshold Cross-modal Modulation of Auditory Response by Cutaneous Electrical Stimulation in First- and Higher-order Auditory Thalamic Nuclei.

Conventional extracellular recording has revealed cross-modal alterations of auditory cell activities by cutaneous electrical stimulation of the hindpaw in first- and higher-order auditory thalamic nuclei (Donishi et al., 2011). Juxta-cellular recording and labeling techniques were used in the present study to examine the cross-modal alterations in detail, focusing on possible nucleus and/or cell type-related distinctions in modulation. Recordings were obtained from 80 cells of anesthetized rats. Cutaneous electrical stimulation, which did not elicit unit discharges, i.e., subthreshold effects, modulated early (onset) and/or late auditory responses of first- (64%) and higher-order nucleus cells (77%) with regard to response magnitude, latency and/or burst spiking. Attenuation predominated in the modulation of response magnitude and burst spiking, and delay predominated in the modulation of response time. Striking alterations of burst spiking took place in higher-order nucleus cells, which had the potential to exhibit higher propensities for burst spiking as compared to first-order nucleus cells. A subpopulation of first-order nucleus cells showing modulation in early response magnitude in the caudal domain of the nucleus had larger cell bodies and higher propensities for burst spiking as compared to cells showing no modulation. These findings suggest that somatosensory influence is incorporated into parallel channels in auditory thalamic nuclei to impose distinct impacts on cortical and subcortical sensory processing. Further, cutaneous electrical stimulation given after early auditory responses modulated late responses. Somatosensory influence is likely to affect ongoing auditory processing at any time without being coincident with sound onset in a narrow temporal window.

Attenuation of pCREB and Egr1 expression in the insular and anterior cingulate cortices associated with enhancement of CFA-evoked mechanical hypersensitivity after repeated forced swim stress.

The perception and response to pain are severely impacted by exposure to stressors. In some animal models, stress increases pain sensitivity, which is termed stress-induced hyperalgesia (SIH). The insular cortex (IC) and anterior cingulate cortex (ACC), which are typically activated by noxious stimuli, affect pain perception through the descending pain modulatory system. In the present study, we examined the expression of phospho-cAMP response element-binding protein (pCREB) and early growth response 1 (Egr1) in the IC and ACC at 3h (the acute phase of peripheral tissue inflammation) after complete Freund's adjuvant (CFA) injection in naïve rats and rats preconditioned with forced swim stress (FS) to clarify the effect of FS, a stressor, on cortical cell activities in the rats showing SIH induced by FS. The CFA injection into the hindpaw induced mechanical hypersensitivity and increased the expression of the pCREB and Egr1 in the IC and ACC at 3h after the injection. FS (day 1, 10min; days 2-3, 20min) prior to the CFA injection enhanced the CFA-induced mechanical hypersensitivity and attenuated the increase in the expression of pCREB and Egr1 in the IC and ACC. These findings suggested that FS modulates the CFA injection-induced neuroplasticity in the IC and ACC to enhance the mechanical hypersensitivity. These findings are thought to signify stressor-induced dysfunction of the descending pain modulatory system.

Bilateral increases in ERK activation at the spinomedullary junction region by acute masseter muscle injury during temporomandibular joint inflammation in the rats.

We determined the role of persistent monoarthritis of temporomandibular joint region (TMJ) on bilateral masseter muscle (MM) nociception in male rats using orofacial nocifensive behaviors, phosphorylated extracellular signal-regulated kinase and Fos induction at the trigeminal subnucleus caudalis/upper cervical spinal cord (Vc/C2) region in response to formalin injection to the MM region. TMJ inflammation was induced by local injection of CFA into the left TMJ region. Orofacial nocifensive behaviors evoked by formalin injection ipsilateral or contralateral to the TMJ inflammation appeared to be increased at 1-14 days or at 1, 10 and 14 days after induction of TMJ inflammation, respectively, while increases in behavioral duration were seen mainly in the late phase rather than the early phase. The number of pERK positive cells was investigated in superficial laminae at the Vc/C2 region at 3, 10, 20, 60 and 80 min after MM stimulation with formalin at 14 days after TMJ inflammation. TMJ-inflamed rats displayed greater responses of pERK expression by the ipsilateral MM stimulation at 3-60 min, while contralateral MM stimulation increased pERK expression at 3, 10 and 20 min compared to non-CFA rats. Fos expression by MM stimulation was increased at 14 days after induction of TMJ inflammation regardless of the affected side. These findings showed that persistent TMJ inflammation for 10 and 14 days is sufficient to enhance MM nociception indicated by behaviors and neural responses in superficial laminae at the Vc/C2 region.

Repeated forced swim stress affects the expression of pCREB and ΔFosB and the acetylation of histone H3 in the rostral ventromedial medulla and locus coeruleus.

The rostral ventromedial medulla (RVM) and locus coeruleus (LC) play crucial roles in descending pain modulation system. In the present study we examined the expression of phospho-cAMP response element-binding protein (pCREB) and ΔFosB and the acetylation of histone H3 in the RVM and LC after forced swim stress (FS) and complete Freund's adjuvant (CFA) injection to clarify changes in descending pain modulatory system in a rat model of stress-induced hyperalgesia. FS (day 1, 10min; days 2-3, 20min) induced a significant increase in the expression of pCREB and ΔFosB and the acetylation of histone H3 in the RVM, whereas the FS induced a significant increase only in the acetylation of histone H3 in the LC. CFA injection into the hindpaw did not induce a significant change in those expression and acetylation. Quantitative image analysis demonstrated that the numbers of pCREB-, acetylated histone H3- and ΔFosB-IR cells in the RVM were significantly higher in the FS group than those in the naive group. The CFA injection after the FS did not affect the FS-induced increases in the expression of pCREB and ΔFosB and the acetylation of histone H3 in the RVM even though nullified the increase in the acetylation of histone H3 in the LC. These findings suggest different neuroplasticities between the RVM and LC after the FS, which may be involved in activity change of descending pain modulatory system after the CFA injection.

Anatomically structured burst spiking of thalamic reticular nucleus cells: implications for distinct modulations of sensory processing in lemniscal and non-lemniscal thalamocortical loop circuitries.

The thalamic reticular nucleus (TRN) occupies a highly strategic position to modulate sensory processing in the thalamocortical loop circuitries. It has been shown that TRN visual cells projecting to first- and higher-order thalamic nuclei have distinct levels of burst spiking, suggesting the possibility that the TRN exerts differential influences on information processing in first- and higher-order thalamic nuclei that compose the lemniscal and non-lemniscal sensory systems, respectively. To determine whether this possibility could extend across sensory modalities, the present study examined activities of TRN auditory cells projecting to the ventral and dorsal divisions (first- and higher-order auditory thalamic nuclei) of the medial geniculate nucleus (TRN-MGV and TRN-MGD cells) in anesthetized rats, using juxta-cellular recording and labeling techniques. Burst spiking of TRN-MGV cells consisted of larger numbers of spikes with shorter inter-spike intervals as compared with that of TRN-MGD cells in auditory response evoked by noise burst stimuli. Similar distinctions, although not statistically significant, were observed in spontaneous activity. Furthermore, the features of burst spiking varied in association with the topographies of cell body and terminal field locations. These features of burst spiking are similar to those observed in the two types of TRN visual cells. First- and higher-order thalamic nuclei are known to have distinct levels of burst spiking across sensory modalities. Taken together, it is suggested that the distinctions in burst spiking in the TRN, in conjunction with those in thalamic nuclei, could constitute distinct circuitries for lemniscal and non-lemniscal sensory processing in the thalamocortical loop.

Auditory thalamic reticular nucleus of the rat: anatomical nodes for modulation of auditory and cross-modal sensory processing in the loop connectivity between the cortex and thalamus.

The auditory sector of the thalamic reticular nucleus (TRN) plays a pivotal role in gain and/or gate control of auditory input relayed from the thalamus to cortex. The TRN is also likely involved in cross-modal sensory processing for attentional gating function. In the present study, we anatomically examined how cortical and thalamic afferents intersect in the auditory TRN with regard to these two functional pathways. Iontophoretic injections of biocytin into subregions of the auditory TRN, which were made with the guidance of electrophysiological recording of auditory response, resulted in retrograde labeling of cortical and thalamic cells, indicating the sources of afferents to the TRN. Cortical afferents from area Te1 (temporal cortex, area 1), which contains the primary and anterior auditory fields, topographically intersected thalamic afferents from the ventral division of the medial geniculate nucleus at the subregions of the auditory TRN, suggesting tonotopically organized convergence of afferents, although they innervated a given small part of the TRN from large parts. In the caudodorsal and rostroventral parts of the auditory TRN, cortical afferents from nonprimary visual and somatosensory areas intersected thalamic afferents from auditory, visual, and somatosensory nuclei. Furthermore, afferents from the caudal insular cortex and the parvicellular part of the ventral posterior thalamic nucleus, which are associated with visceral processing, converged to the rostroventral end of the auditory TRN. The results suggest that the auditory TRN consists of anatomical nodes that mediate tonotopic and/or cross-modal modulation of auditory and other sensory processing in the loop connectivity between the cortex and thalamus.

Activation of mitogen-activated protein kinase in descending pain modulatory system.

The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) influence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identification of novel targets for a variety of pain syndromes.

Involvement of descending facilitation from the rostral ventromedial medulla in the enhancement of formalin-evoked nocifensive behavior following repeated forced swim stress.

In the present study we examined whether the descending facilitation from the rostral ventromedial medulla (RVM) is required for the enhancement of formalin-evoked nocifensive behavior following repeated forced swim stress. Rats were subjected to forced or sham swim stress for 3days. Withdrawal latency to noxious thermal stimuli and mechanical withdrawal threshold to von Frey filaments did not change significantly in both groups at 24h after the last stress session. The forced swim stress showed significantly enhanced nocifensive behavior to the subcutaneous administration of formalin at 2days after the last stress session (1330.1+/-62.8s), compared to the sham swim (1076+/-102.4s, p<0.05) and naive groups (825.9+/-83.2s, p<0.01). The destruction of the RVM with ibotenic acid led to prevent the enhancement of formalin-evoked nocifensive behavior in the forced swim group. These findings suggest that the descending facilitation from the RVM may be involved in the enhancement of formalin-evoked nocifensive behavior following the forced swim stress.

Axonal projections of auditory cells with short and long response latencies in the medial geniculate nucleus: distinct topographies in the connection with the thalamic reticular nucleus.

The thalamic reticular nucleus (TRN) is a crucial anatomical node of thalamocortical connectivity for sensory processing. In the rat auditory system, we determined features of thalamic projections to the TRN, using juxtacellular recording and labeling techniques. Two types of auditory cells (short latency, SL, and long latency, LL), exhibiting unit discharges to noise burst stimuli (duration, 100 ms) with short (< 50 ms) and long (> 100 ms) response latencies, were obtained from the ventral division of the medial geniculate nucleus (MGV). Both SL and LL cells had a propensity to exhibit reverberatory discharges in response to sound stimuli. The primary discharges of SL cells were mostly single spikes while the non-primary discharges of SL cells and the whole discharges of LL cells were mostly burst spikes. SL cells sent topographic projections to the TRN along the dorsoventral and rostrocaudal neural axes while LL cells only along the rostrocaudal axis. As tonotopy-related cortical projections to the TRN are topographic primarily along the dorsoventral extent of the TRN and the MGV is tonotopically organized along the dorsoventral axis, SL cells, directly activated by ascending auditory inputs, may be closely involved in tonotopic thalamocortical connectivity. On the other hand, LL cells, which are suppressed by ascending inputs and could be driven to discharge by corticofugal inputs, are assumed to activate the TRN in a manner less related to tonotopic organization. There may exist heterogeneous projections from the MGV to the TRN, which, in conjunction with corticofugal connections, could constitute distinct channels of auditory processing.

Activation of ERK in the locus coeruleus following acute noxious stimulation.

In the present study, the activation of extracellular signal-regulated kinase (ERK) in the locus coeruleus (LC) following injection of formalin or complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after acute noxious stimulation or chronic inflammation. In naive rats there were few phospho-extracellular signal-regulated kinase-immunoreactive (p-ERK-IR) neurons in the LC. Formalin-, CFA- and saline-injections induced an increase in p-ERK-IR in the LC. The number of p-ERK-IR neurons in the LC in the formalin group was significantly higher than those in all other groups from 5 min to 1 h after the injection (p<0.05). CFA injection induced only a transient significant increase in the number of p-ERK-IR neurons and there was no significant difference in the number of p-ERK-IR neurons between the CFA and saline groups. At 5 min after formalin injection, almost all p-ERK-IR neurons in the LC were tyrosine hydroxylase (TH) -positive. These findings suggest that activation of ERK in the LC is induced by acute noxious stimulation, such as formalin injection, but not by CFA-induced chronic inflammation. The activation of ERK in the LC may be involved in the plasticity of the descending pain modulatory systems following acute noxious stimulation.

[Descending facilitation in chronic stress and chronic pain state].

The spino-thalamic tract consists of two systems; the lateral system terminates in the somato-sensory cortex, and participates in the sensory discrimination of pain, and the medial system terminates in the anterior cingulated cortex (ACC) and insular cortex (IC) to mediate affective components of pain. Persistent pain induces plastic changes in cortical neurons, especially in the ACC and IC. Activation of these neurons is transmitted to the periaqueductal gray and rostroventromedial medulla (RVM) (descending pain control system). This system has long been considered to exert descending inhibition, but recent studies revealed that it also causes facilitation in certain pathological conditions. A variety of stressful stimuli have been shown to affect pain sensitivity. We demonstrated that chronic restraint stress induced thermal hyperalgesia in rats, in which phosphorylated ERK and levels of tryptophan hydroxylase, a key enzyme of 5-HT production, were increased in the RVM. 5HT released from the bulbospinal neurons may exert facilitatory effects on spinal nociceptive processing probably through 5HT3 receptors. Patients suffering chronic pain originating from deep tissues, such as temporo-mandibular disorder, fibromyalgia, or low back pain, often complain of pain and tenderness in various parts of the body. We injected complete Freund's adjuvant into a temporo-mandibular joint of rats unilaterally, and then injected 5% formalin into the ipsilateral or contralateral masseter muscle 2 weeks later. Pain-related behavior and neuronal activation in the spinal trigeminal nucleus were enhanced on both sides compared to those in non-inflammatory controls. Systemic enhancement of pain and hyperalgesia induced by unilateral joint inflammation may have been caused by the central sensitization and descending facilitation.

Activation of ERK in the rostral ventromedial medulla is involved in hyperalgesia during peripheral inflammation.

We have previously shown that the extracellular signal-regulated kinase (ERK) is activated in the rostral ventromedial medulla (RVM) during peripheral inflammation. In the present study, the relationship between ERK signaling in the RVM and pain hypersensitivity was investigated in the rat. Microinjection of U0126, a mitogen-activated protein kinase kinase inhibitor, into the RVM decreased phosphorylated ERK at 7 h after complete Freund's adjuvant (CFA) injection into the hindpaw. The U0126 microinjection also attenuated thermal hyperalgesia in the ipsilateral hindpaw at 24 h after CFA injection. The ipsilateral paw withdrawal latency in the U0126 group (67.9%+/-5.3% vs. baseline, n=7) was significantly longer than that in the control group (52.0%+/-3.6% vs. baseline, n=8). These findings suggest that activation of ERK in the RVM contributes to thermal hyperalgesia during peripheral inflammation.

Effects of peripheral inflammation on activation of p38 mitogen-activated protein kinase in the rostral ventromedial medulla.

In the present study, the activation of p38 mitogen-activated protein kinase (p38 MAPK) in the rostral ventromedial medulla (RVM) following the injection of complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after peripheral inflammation. Phospho-p38 MAPK-immunoreactive (p-p38 MAPK-IR) neurons were observed in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (GiA). Inflammation induced the activation of p38 MAPK in the RVM, with a peak at 30 min after the injection of CFA into the hindpaw, which lasted for 1 h. In the RVM, the number of p-p38 MAPK-IR neurons per section in rats killed at 30 min after CFA injection (19.4+/-2.0) was significantly higher than that in the naive group (8.4+/-2.4) [p<0.05]. At 30 min after CFA injection, about 40% of p-p38 MAPK-IR neurons in the RVM were serotonergic neurons (tryptophan hydroxylase, TPH, positive) and about 70% of TPH-IR neurons in the RVM were p-p38 MAPK positive. The number of p-p38 MAPK- and TPH-double-positive RVM neurons in the rats with inflammation was significantly higher than that in naive rats [p<0.05]. These findings suggest that inflammation-induced activation of p38 MAPK in the RVM may be involved in the plasticity in the descending pain modulatory system following inflammation.

TMJ inflammation increases Fos expression in the nucleus raphe magnus induced by subsequent formalin injection of the masseter or hindpaw of rats.

The study was designed to examine the effect of persistent temporomandibular joint (TMJ) inflammation on neuronal activation in the descending pain modulatory system in response to noxious stimulus. Formalin was injected into the left masseter muscle or hindpaw of rats 10 days after injection of the left TMJ with saline or complete Freund's adjuvant (CFA). The results showed that 10-day persistent TMJ inflammation (induced by CFA) alone did not induce a significant increase in Fos-like immunoreactive (Fos-LI) neurons in the rostral ventromedial medulla (RVM) or locus coeruleus (LC), but that formalin injection of the masseter muscle or hindpaw induced a significant increase in Fos-LI neurons in the RVM and LC of rats with and without TMJ inflammation (P < 0.05). However, persistent TMJ inflammation significantly increased Fos-LI neurons in the nucleus raphe magnus (NRM) induced by subsequent formalin injection of the masseter muscle and hindpaw (70.2% increase and 53.8% increase, respectively, over the control TMJ-saline-injected rats; P < 0.05). The results suggest that persistent TMJ inflammation increases neuronal activity, in particularly in the NRM, by the plastic change of the descending pain modulatory system after ipsilateral application of a noxious stimulus to either orofacial area or a spatially remote body area.

Increased body weight in mice lacking mu-opioid receptors.

Opioids have been suggested to affect feeding behaviour. To clarify the role of mu-opioid receptors in feeding, we measured several parameters relating to food intake in mu-opioid receptor knockout mice. Here, we show that the knockout mice had increased body weight in adulthood, although the intake amount of standard food was similar between the wild-type and knockout littermates. Serum markers for energy homeostasis were not significantly altered in the knockout mice. Hypothalamic neuropeptide Y mRNA, however, was higher in knockouts than in wild-type mice. Our results suggest that the up-regulated expression of neuropeptide Y mRNA might contribute to the increased weights of adult mu-opioid receptor knockout mice.

Stress-induced hyperalgesia: animal models and putative mechanisms.

Stress has been shown to affect brain activity and promote long-term changes in multiple neural systems. A variety of environmental and/or stressful stimuli have been shown to produce analgesia, a phenomenon often referred to as stress-induced analgesia (SIA). However, acute and chronic stresses also produce hyperalgesia in various behavioral tests. There are now several animal models in which stress enhances nociceptive responses. The dysfunction of the hypothalamo-pituitary-adrenocortical axis (HPA axis) and multiple neurotransmitter systems in the central nervous system (CNS), including endogenous opioid, serotonergic and noradrenergic systems, has been reported. These stress-induced hyperalgesia models may contribute to a better understanding of chronic pain and provide a more rational basis for drug therapies in a variety of pain syndromes.