Responses of neurons in rostral ventromedial medulla to nociceptive stimulation of craniofacial region and tail in rats.

The rostral ventromedial medulla (RVM) plays a key role in the endogenous modulation of nociceptive transmission in the central nervous system (CNS). The primary aim of this study was to examine whether the activities of RVM neurons were related to craniofacial nociceptive behaviour (jaw-motor response, JMR) as well as the tail-flick response (TF). The activities of RVM neurons and TF and JMR evoked by noxious heating of the tail or perioral skin were recorded simultaneously in lightly anaesthetized rats. Tail or perioral heating evoked the TF and JMR, and the latency of the JMR was significantly shorter (P < 0.001) than that of the TF. Of 89 neurons recorded in RVM, 40 were classified as ON-cells, 27 as OFF-cells, and 22 as NEUTRAL-cells based on their responsiveness to heating of the tail. Heating at either site caused an increase in ON-cell and decrease in OFF-cell activity before the occurrence of the TF and JMR, but did not alter the activity of NEUTRAL cells. Likewise, noxious stimulation of the temporomandibular joint had similar effects on RVM neurons. These findings reveal that the JMR is a measure of the excitability of trigeminal and spinal nociceptive circuits in the CNS, and that the JMR as well as TF can be used for studying processes related to descending modulation of pain. The findings also support the view that RVM ON- and OFF-cells play an important role in the elaboration of diverse nociceptive behaviours evoked by noxious stimulation of widely separated regions of the body.

Involvement of 5-HT2A, 5-HT2B and 5-HT2C receptors in mediating the ventrolateral orbital cortex-induced antiallodynia in a rat model of neuropathic pain.

The present study examined the roles of 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes in mediating the ventrolateral orbital cortex (VLO)-induced antiallodynia in a rat model of neuropathic pain induced by spared nerve injury (SNI). Change of mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of preferential or selective 5-HT2A/C, 5-HT2B and 5-HT2C receptor agonists, (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), α-methyl-5-(2-thienylmethoxy)-1H-Indole-3-ethanamine hydrochloride (BW723C86) and 1-(3-Chlorophenyl)-piperazine hydrochloride (m-CPP) into the VLO significantly depressed allodynia induced by SNI, and the inhibitory effect of DOI was blocked or attenuated by selective 5-HT2A/C receptor antagonists ketanserin (+)-tartrate salt (ketanserin) and 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907); the effects of BW723C86 and m-CPP were antagonized by 5-HT2B receptor antagonists N-(1-Methyl-1H-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea (SB204741) and 5-HT2C receptor antagonist RS102221 hydrochloride hydrate (RS-102221), respectively. These results suggest that 5-HT2A, 5-HT2B, 5-HT2C receptor subtypes are involved in mediating the VLO-induced antiallodynia in the neuropathic pain state.

Activation of α1 adrenoceptors in ventrolateral orbital cortex attenuates allodynia induced by spared nerve injury in rats.

Recent studies have demonstrated that noradrenaline acting in the ventrolateral orbital cortex (VLO) can potentially reduce allodynia induced by spared nerve injury (SNI), and this effect is mediated by α2 adrenoceptor. The present study examined the effect of the α1 adrenoceptors in the VLO on allodynia induced by SNI in the rats. The mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of selective α1 adrenoceptor agonist methoxamine (20, 50, 100 µg in 0.5 µl) into the VLO, contralateral to the site of nerve injury, increased PWT in a dose-dependent manner. This effect was antagonized by pre-microinjection of the selective α1 adrenoceptor antagonist benoxathian into the same VLO site, and blocked by electrolytic lesion of the ventrolateral periaqueductal gray (PAG). Furthermore, pre-administration of non-selective glutamate receptor antagonist kynurenic acid, phospholipase C (PLC) inhibitor U73122, and protein kinase C (PKC) inhibitor chelerythrine to the VLO also blocked methoxamine-induced inhibition of allodynia. These results suggest that activation of α1 adrenoceptors in the VLO can potentially reduce allodynia induced by SNI. This effect may be direct excitation of the VLO neurons, via PLC-PKC signaling pathway, projecting to the PAG or facilitating glutamate release and then indirectly exciting the VLO output neurons projecting to the PAG, leading to activation of the PAG-brainstem descending inhibitory system which depresses the nociceptive transmission at the spinal cord level.

Administration of somatostatin analog octreotide in the ventrolateral orbital cortex produces sex-related antinociceptive effects on acute and formalin-induced nociceptive behavior in rats.

The present study was designed to examine whether somatostatin analog octreotide (OCT) was involved in antinociception in the ventrolateral orbital cortex (VLO) and determine whether this effect had a sex difference between male and female rats. The radiant heat-evoked tail flick (TF) reflex was used as an index of acute nociceptive response in lightly anesthetized rats. The number of flinches evoked by formalin injection into the hindpaw was used to evaluate inflammatory persistent pain in conscious rats. Administration of OCT (2.0, 5.0 10.0 ng in 0.5 µl) into the VLO depressed the TF reflex in a dose-dependent manner only in female rats, but not male rats. Pretreatment with a nonselective somatostatin receptor antagonist cyclo-somatostatin (c-SOM) (25.0 µg in 0.5 µl) into the VLO antagonized 10.0 ng OCT-induced inhibition of the TF reflex in female rats. Similarly, application of high dose of OCT (10.0 ng in 0.5 µl) into the VLO depressed formalin-induced flinching response in the early and late phases only in female rats, and had no any effects in male rats. Pretreatment with c-SOM (25.0 µg in 0.5 µl) into the VLO totally antagonized the 10 ng OCT-induced inhibition of the flinches in both phases in female rats. Additionally, single administration of c-SOM into the VLO failed to alter tail reflex latencies and formalin-induced nociceptive behaviors in female rats. The results provide the first valuable evidence that somatostatin and its receptors are involved in antinociception in acute heat-evoked nociception and inflammatory persistent pain only in female rats, not male rats, in the VLO.

Activation of mu-opioid receptors in the ventrolateral orbital cortex inhibits the GABAergic miniature inhibitory postsynaptic currents in rats.

Previous studies have indicated that mu-opioid receptors in the ventrolateral orbital cortex (VLO) are involved in antinociception in tail flick tests and GABAergic neurons or terminals express mu-opioid receptors in the VLO. The current study examined the effect of selective mu-opioid receptor agonist DAMGO on the GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in the VLO in rats using the whole-cell patch clamp. The results demonstrated that 5 µM DAMGO application into the rat VLO slices significantly reduced the GABAergic mIPSCs frequency, without any effect on its amplitude, and this effect of DAMGO was reversed by pretreatment with selective mu-opioid receptor antagonist 1 µM CTOP. Importantly, application of CTOP alone into the VLO slices did not produce any effect on the frequency and amplitude of GABAergic mIPSCs. These results indicate a presynaptic effect of mu-opioid receptor activation on the GABAergic neurons in the VLO. The current data suggests that a presynaptic inhibition of the GABA release may contribute to the mu-opioid receptor mediated effects in the VLO and provides novel electrophysiological evidence for the underlying mechanisms of mu-opioid receptors in the VLO.

The role of α2 adrenoceptor in mediating noradrenaline action in the ventrolateral orbital cortex on allodynia following spared nerve injury.

The present study examined the role of α2 adrenoceptor in mediating noradrenaline action in the ventrolateral orbital cortex (VLO) on allodynia induced by spared nerve injury (SNI) in the rat. The mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of noradrenaline (1, 2, 4 µg in 0.5 µl) into the VLO, contralateral to the site of nerve injury, reduced allodynia; PWT increased in a dose-dependent manner. Similar to noradrenaline, microinjection of selective α2 adrenoceptor agonist clonidine into the same VLO site also reduced allodynia, and was blocked by selective α2 adrenoceptor antagonist yohimbine. Furthermore, administration of γ-aminobutyric acid A (GABAA) receptor antagonist bicuculline or picrotoxin to the VLO significantly enhanced clonidine-induced inhibition of allodynia, while GABAA receptor agonist muscimol or THIP (2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride) attenuated clonidine-induced inhibition. These results suggest that noradrenaline acting in the VLO can potentially reduce allodynia induced by SNI, and this effect is mediated by α2 adrenoceptor. Moreover, GABAergic disinhibition may participate in α2 receptor mediating effects in neuropathic pain in the central nervous system.

Lateral reticular nucleus modulates the cardiosomatic reflex evoked by intrapericardial capsaicin in the rat.

The current study examined the role of the lateral reticular nucleus (LRN) in modulating the cardiosomatic reflex (CSR) induced by intrapericardial capsaicin in the anesthetized rat. Intrapericardial capsaicin was administered, and the CSR was monitored via electromyogram responses of the dorsal spinotrapezius muscle. Electrical stimulation of the LRN (10, 20 and 30 µA) depressed the CSR induced by intrapericardial capsaicin in an intensity-dependent manner. Microinjection of glutamate (4, 10, 20 and 40 nmol, in 0.2 µL) into the LRN replicated the effects of electrical stimulation. Furthermore, bilateral transections of the dorsolateral funiculus (DLF) decreased the LRN electrical stimulation-induced inhibition of the electromyogram responses. Intrathecal administration of the α2 -adrenergic receptor antagonist yohimbine or the serotonergic receptor antagonist methysergide significantly attenuated the LRN electrical stimulation-induced inhibition of the electromyogram responses. However, intrathecal application of the opioid receptor antagonist naloxone had no effect on the LRN electrical stimulation-induced inhibition. These results suggest that the LRN-DLF-spinal cord pathway is involved in descending inhibition of the CSR, and spinal α2 -adrenergic and serotonergic receptors participate in this descending inhibition.

The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model.

The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0µg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (raclopride, 3.0µg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0µg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2)-like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0µg) into the same VLO site, and this effect was antagonized by raclopride (3.0µg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0µg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10µg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1)-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception.

Diabetic rats show reduced cardiac-somatic reflex evoked by intrapericardial capsaicin.

Painless myocardial infarction is a serious complication of diabetes. The present study examined whether cardiac nociception was altered in the streptozotocin-induced diabetic rat model by assessing intrapericardial capsaicin-evoked electromyography (EMG) responses in the spinotrapezius muscle. Somatic sensitivities to mechanical and thermal stimulation of the skin were also determined. Intrapericardial administration of capsaicin evoked a concentration-dependent EMG response, which was reproducible with repeated administration. However, the capsaicin-induced EMG responses were different in streptozotocin-induced diabetic rats and controls. Intrapericardial capsaicin produced fewer EMG responses, which were delayed and reduced in streptozotocin-treated rats compared to controls. Pretreatment with capsazepine, a TRPV1 antagonist, significantly decreased capsaicin-evoked EMG activity in both streptozotocin-treated and control rats. In addition, streptozotocin-treated rats showed a decreased paw withdrawal threshold in response to mechanical stimulation but no change in response to radiant heat stimulation. These results suggest that streptozotocin-induced diabetic rats develop somatic mechanical hypersensitivity (allodynia), but reduced cardiac nociception. Decreased TRPV1 function may contribute to the reduction of cardiac nociception in the diabetic rat.

Activation of serotonin 1A receptors in ventrolateral orbital cortex depresses persistent nociception: a presynaptic inhibition mechanism.

The present study examined the effect of serotonin 1A (5-HT(1A)) receptor activation in the ventrolateral orbital cortex (VLO) upon formalin-evoked flinching behavior and spinal Fos expression, and further determined whether activation of 5-HT(1A) receptors affected the spontaneous GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in rat VLO slice by pharmacologically separated neurons to understand the possible mechanism underlying this effect. Microinjection of the 5-HT(1A) receptors agonist 8-OH-DPAT (8-hydro-2-(di-n-propylamino) tetralin) into the VLO depressed the formalin-evoked nociceptive behavior flinching response and the Fos expression in the lumbar spinal cord dorsal, which was antagonized by pre-treatment with 5-HT(1A) receptors antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide). Furthermore, application of 8-OH-DPAT into VLO slice inhibited GABAergic mIPSC frequency in a dose-dependent manner without effects on amplitude of the GABAergic mIPSCs, this effect was blocked by NAN-190. These results provide evidence for the involvement of 5-HT(1A) receptors in VLO in the modulation of persistent inflammatory nociception, and suggest that a presynaptic inhibition of the GABA release may contribute to the 5-HT(1A) receptor-mediated descending antinociception.

The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: a novel pain modulation pathway.

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG-brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm-VLO-PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-delta and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of mu-opioid receptors, serotonin 1(A) receptors, and dopamine D(2)-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.

Bradykinin is involved in the mediation of cardiac nociception during ischemia through upper thoracic spinal neurons.

Bradykinin is one of metabolites produced during myocardial ischemia and infarction that can activate cardiac spinal (sympathetic) sensory neurons to cause chest pain. The aim of this study was 1) to characterize the responses of thoracic superficial and deeper spinal neurons in rats to intrapericardial administration of bradykinin as a noxious cardiac stimulus; 2) to compare neuronal responses to bradykinin alone and a mixture of algogenic chemicals (serotonin, prostaglandin E(2), histamine, adenosine and bradykinin) used in a previous study. Extracellular potentials of single neurons in the T(3) spinal cord were recorded in pentobarbital anesthetized, paralyzed, and ventilated male rats. A catheter was placed in the pericardial sac to administer 0.2 ml solution of bradykinin (10(-5) M, 1 min). The results showed that 10/33 (30%) superficial and 80/165 (48%) deeper spinal neurons responded to intrapericardial bradykinin. All 10 superficial responsive neurons and 72/80 (90%) deeper neurons were excited; 7 (9%) neurons were inhibited; one neuron showed excitation-inhibition response pattern. Of 72 neurons excited by bradykinin, 35 and 47 neurons exhibited short- and long-lasting responses patterns, respectively. The proportions of response patterns and maximal excitatory responses to bradykinin were similar to effects obtained with a mixture of algogenic chemicals. However, the time to peak (28.3+/-3.1 s) and recovery time of long-lasting excitatory responses to bradykinin alone (125.2+/-8.9 s, n=47) were significantly shorter than the responses of neurons to the algogenic mixture (38.6+/-3.8 s and 187.5+/-18.5 s, n=49, P<0.05). In conclusion, bradykinin might play a key role in spinal processing for cardiac nociception, although other components released during ischemia might affect time characteristics of a subtype of thoracic spinal neurons receiving noxious cardiac input.

D2-like but not D1-like dopamine receptors are involved in the ventrolateral orbital cortex-induced antinociception: a GABAergic modulation mechanism.

The ventrolateral orbital cortex (VLO) is part of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius (Sm) and a descending pathway to the spinal cord relaying in the periaqueductal gray (PAG). This study examines whether activation of D(1)-like and D(2)-like dopamine receptors in VLO produces antinociception and whether GABAergic modulation is involved in the VLO, D(2)-like dopamine receptor activation-evoked antinociception. The radiant heat-evoked tail flick (TF) reflex was used as an index of nociceptive response in lightly anesthetized rats. Microinjection of the D(2)-like (D(2)/D(3)) dopamine receptor agonist quinpirole (0.1-2.0 microg), but not D(1)-like (D(1)/D(5)) receptor agonist SKF-38393 (1.0, 5.0 microg), into VLO produced dose-dependent antinociception which was antagonized by the D(2)-like (D(2)/D(3)) receptor antagonist raclopride (1.5 microg). We also found that VLO application of the GABA(A) receptor antagonist bicuculline or picrotoxin (100 ng) enhanced the quinpirole-induced inhibition of the TF reflex, whereas the GABA(A) receptor agonist muscimol (250 ng) or THIP (1.0 microg) significantly attenuated the quinpirole-induced inhibition. These results suggest that D(2)-like, but not D(1)-like, dopamine receptors are involved in VLO-induced antinociception and that GABAergic disinhibitory mechanisms participate in the D(2)-like receptor mediated effect. These findings provide support for the hypothesis that D(2)-like receptor activation may inhibit the inhibitory action of the GABAergic interneurons on the output neurons projecting to PAG leading to activation of the brainstem descending inhibitory system and depression of nociceptive inputs at the spinal dorsal horn.

Synaptic connections between GABAergic elements and serotonergic terminals or projecting neurons in the ventrolateral orbital cortex.

The ventrolateral orbital cortex (VLO) is part of an endogenous analgesic system, consisting of the spinal cord-thalamic nucleus submedius-VLO periaqueductal gray (PAG)-spinal cord loop. The present study examined morphological connections of GABAergic (gamma-aminobutyric acidergic) neurons and serotonergic projection terminals from the dorsal raphe nucleus (DR), as well as the relationship between GABAergic terminals and VLO neurons projecting to the PAG, by using anterograde and retrograde tracing combined with immunofluorescence, immunohistochemistry, and electron microscopy methods. Results indicate that the majority (93%) of GABAergic neurons in the VLO also express the 5-HT(1A) (5-hydroxytryptamine 1A) receptor, and serotonergic terminals originating from the DR nucleus made symmetrical synapses with GABAergic neuronal cell bodies and dendrites within the VLO. GABAergic terminals also made symmetrical synapses with neurons expressing GABA(A) receptors and projecting to the PAG. These results suggest that a local neuronal circuit, consisting of 5-HTergic terminals, GABAergic interneurons, and projection neurons, exists in the VLO, and provides morphological evidence for the hypothesis that GABAergic modulation is involved in 5-HT(1A) receptor activation-evoked antinociception.

Cerebral cortex modulation of pain.

Pain is a complex experience encompassing sensory-discriminative, affective-motivational and cognitiv e-emotional components mediated by different mechanisms. Contrary to the traditional view that the cerebral cortex is not involved in pain perception, an extensive cortical network associated with pain processing has been revealed using multiple methods over the past decades. This network consistently includes, at least, the anterior cingulate cortex, the agranular insular cortex, the primary (SI) and secondary somatosensory (SII) cortices, the ventrolateral orbital cortex and the motor cortex. These cortical structures constitute the medial and lateral pain systems, the nucleus submedius-ventrolateral orbital cortex-periaqueductal gray system and motor cortex system, respectively. Multiple neurotransmitters, including opioid, glutamate, GABA and dopamine, are involved in the modulation of pain by these cortical structures. In addition, glial cells may also be involved in cortical modulation of pain and serve as one target for pain management research. This review discusses recent studies of pain modulation by these cerebral cortical structures in animals and human.

Microinjection of morphine into thalamic nucleus submedius depresses bee venom-induced inflammatory pain in the rat.

Previous studies have provided evidence of the existence of a pain modulatory feedback pathway consisting of thalamic nucleus submedius (Sm)-ventrolateral orbital cortex-periaqueductal grey pathway, which is activated during acute pain and leads to depression of transmission of nociceptive information in the spinal dorsal horn. The aim of this study was to test the hypothesis that morphine microinjection into the Sm decreased spontaneous pain and bilateral thermal hyperalgesia, as well as ipsilateral mechanical allodynia, induced by subcutaneous injections of bee venom into the rat hind paw. Morphine (1.0, 2.5 or 5.0 microg in 0.5 microL) injected into the Sm, contralateral to the bee venom-injected paw, depressed spontaneous nociceptive behaviour in a dose-dependent manner. Furthermore, morphine significantly decreased bilateral thermal hyperalgesia and ipsilateral mechanical allodynia 2 h after bee venom injection. These morphine-induced effects were antagonized by 1.0 microg naloxone (an opioid antagonist) microinjected into the Sm 5 min before morphine administration. The results provided further support for the important role of the Sm and Sm-opioid receptors in inhibiting nociceptive behaviour and indicated for the first time that Sm opioid receptors were also effective in inhibiting the hypersensitivity provoked by bee venom-induced inflammation.

GABAergic modulation is involved in the ventrolateral orbital cortex 5-HT 1A receptor activation-induced antinociception in the rat.

The ventrolateral orbital cortex (VLO) is a component of an endogenous analgesic system consisting of an ascending pathway from the spinal cord to VLO via the thalamic nucleus submedius (Sm) and a descending pathway relaying in the periaqueductal gray matter (PAG). This study examines whether the activation of 5-HT 1A receptors in VLO produces antinociception and whether GABAergic modulation is involved in the VLO 5-HT 1A receptor activation-evoked antinociception. The radiant heat-evoked tail flick (TF) reflex was used as an index of nociceptive response in lightly anesthetized rats. Microinjection of the 5-HT 1A receptor agonist 8-OH-DPAT (1.0, 2.0, 5.0 microg) into VLO produced dose-dependent antinociception, which was reversed by the 5-HT 1A receptor antagonist (NAN-190, 20 mug). We also found that VLO application of the GABA A receptor antagonist bicuculline or picrotoxin (100 ng) enhanced the 8-OH-DPAT-induced inhibition of the TF reflex, whereas the GABA A receptor agonist muscimol (250 ng) or THIP (1.0 microg) significantly attenuated the 8-OH-DPAT-induced inhibition. These results suggest that 5-HT 1A receptors are involved in VLO-induced antinociception and that GABAergic disinhibitory mechanisms participate in the 5-HT 1A receptor-mediated effect. These findings provide support for the hypothesis that 5-HT 1A receptor activation may inhibit the inhibitory action of the GABAergic interneurons on the output neurons projecting to PAG leading to activation of the brainstem descending inhibitory system and depression of nociceptive inputs at the spinal cord level.

Mu-opioid receptor in the nucleus submedius: involvement in opioid-induced inhibition of mirror-image allodynia in a rat model of neuropathic pain.

The current study investigated the roles of various subtypes of opioid receptors expressed in the thalamic nucleus submedius (Sm) in inhibition of mirror-image allodynia induced by L5/L6 spinal nerve ligation in rats. Morphine was microinjected into the Sm, which produced a dose-dependent inhibition of mirror-image allodynia; this effect was antagonized by pretreatment with non-selective opioid receptor antagonist naloxone. Microinjections of endomorphin-1 (mu-receptor agonist), or [D-Ala(2), D-Leu(5)]-enkephalin (DADLE, delta-/mu-receptor agonist), also inhibited mirror-image allodynia, and these effects were blocked by the selective mu-receptor antagonist, beta-funaltrexamine hydrochloride. The DADLE-induced inhibition, however, was not influenced by the delta-receptor antagonist naltrindole. The kappa-receptor agonist, spiradoline mesylate salt, failed to alter the mirror-image allodynia. These results suggest that Sm opioid receptor signaling is involved in inhibition of mirror-image allodynia; this effect is mediated by mu- (but not delta- and kappa-) opioid receptors in the rat model of neuropathic pain.

Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement.

In order to explore a novel method for the treatment of drug abuse, we evaluated the effect of chronic deep brain stimulation (DBS) of the rat nucleus accumbens (NAc) on morphine reinforcement, using a DBS apparatus and an implant method we developed. Thirty-two adult rats weighing 240-260 g were divided into three groups, which included a DBS group (n = 10, administration of surgery, morphine and DBS), a sham DBS group (n = 12, administration of surgery and morphine) and a control group (n = 10, administration of physiological saline). The DBS electrode was stereotaxically implanted into the core of unilateral NAc and connected to an implantable pulse generator. Then, they were fixed to the rat skull. One week later, the rats in each group were intraperitoneally injected with morphine at an increasing dose (10-60 mg/kg) once daily. The rats in the DBS group were administered a 130-Hz high-frequency stimulation (HFS) once daily. A 900-second conditioned place preference (CPP) paradigm was used for determining the effect of electrical stimulation on morphine reinforcement in rats. The data showed that 7-10 days later, the preference score of the DBS group was significantly lower than that of the sham DBS group. The results suggest that chronic HFS of the rat NAc can block CPP induced by morphine and attenuate morphine reinforcement.

[Roles of ventrolateral orbital cortex in pain modulation and acupuncture analgesia].

The ventrolateral orbital cortex (VLO) is a major component of orbital cortex, which has extensive connections with periaqueductal gray (PAG), thalamus and other cortical regions. Researches suggest that the VLO is involved not only in nociception, but also in pain modulation, through activation of PAG brainstem descending antinociceptive pathway to inhibit the nociceptive inputs at the spinal/trigeminal level. Furthermore, many results demonstrate that opioid, 5-HT, GABA and their receptors are involved in the VLO antinociception. VLO plays an important role in acupuncture analgesia. In this review we summarized the roles of ventrolateral orbital cortex in pain modulation and acupuncture antinociception.