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• W2015480400 abstract "Opioid receptors in the central nervous system are important modulators of itch transmission. In this study, we examined the effect of mixed-action opioid butorphanol on histamine itch, cowhage itch, and heat pain in healthy volunteers. Using functional MRI, we investigated significant changes in cerebral perfusion to identify the critical brain centers mediating the antipruritic effect of butorphanol. Butorphanol suppressed the itch induced experimentally with histamine, reduced the intensity of cowhage itch by approximately 35%, and did not affect heat pain sensitivity. In comparison with the placebo, butorphanol produced a bilateral deactivation of claustrum, insula, and putamen, areas activated during itch processing. Analysis of cerebral perfusion patterns of brain processing of itch versus itch inhibition under the effect of the drug revealed that the reduction in cowhage itch by butorphanol was correlated with changes in cerebral perfusion in the midbrain, thalamus, S1, insula, and cerebellum. The suppression of histamine itch by butorphanol was paralleled by the activation of nucleus accumbens and septal nuclei, structures expressing high levels of kappa opioid receptors. In conclusion, important relays of the mesolimbic circuit were involved in the inhibition of itch by butorphanol and could represent potential targets for the development of antipruritic therapy. Opioid receptors in the central nervous system are important modulators of itch transmission. In this study, we examined the effect of mixed-action opioid butorphanol on histamine itch, cowhage itch, and heat pain in healthy volunteers. Using functional MRI, we investigated significant changes in cerebral perfusion to identify the critical brain centers mediating the antipruritic effect of butorphanol. Butorphanol suppressed the itch induced experimentally with histamine, reduced the intensity of cowhage itch by approximately 35%, and did not affect heat pain sensitivity. In comparison with the placebo, butorphanol produced a bilateral deactivation of claustrum, insula, and putamen, areas activated during itch processing. Analysis of cerebral perfusion patterns of brain processing of itch versus itch inhibition under the effect of the drug revealed that the reduction in cowhage itch by butorphanol was correlated with changes in cerebral perfusion in the midbrain, thalamus, S1, insula, and cerebellum. The suppression of histamine itch by butorphanol was paralleled by the activation of nucleus accumbens and septal nuclei, structures expressing high levels of kappa opioid receptors. In conclusion, important relays of the mesolimbic circuit were involved in the inhibition of itch by butorphanol and could represent potential targets for the development of antipruritic therapy. arterial spin labeling nucleus accumbens periaqueductal gray matter Recent advances in functional MRI (fMRI) have enabled the visualization of brain responses evoked by itch stimulation. Arterial spin labeling (ASL) is a suitable technique capable of capturing the long-lasting effect of itch on cerebral activity. ASL has evolved from a 2-dimensional to a 3-dimensional technique, such as the 3-D Grase (gradient echo and spin echo)—Propeller (periodically rotated parallel lines with enhanced reconstruction) used in this study (Tan et al., 2011Tan H. Hoge W.S. Hamilton C.A. et al.3D GRASE PROPELLER: improved image acquisition technique for arterial spin labeling perfusion imaging.Magn Reson Med. 2011; 66: 168-173Crossref PubMed Scopus (24) Google Scholar). Previously, ASL was successfully employed to analyze and compare cerebral activations evoked by histamine and cowhage itches (Papoiu et al., 2012Papoiu A.D.P. Coghill R.C. Kraft R.A. et al.A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar) or the mechanisms of itch relief provided by active versus passive scratching (Papoiu et al., 2013Papoiu A.D.P. Nattkemper L.A. Sanders K.M. et al.Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching.PLoS One. 2013; 8: e82389Crossref PubMed Scopus (83) Google Scholar). Moreover, ASL enables the comparative analysis of itch responses evoked in healthy individuals and chronic itch sufferers (Ishiuji et al., 2009Ishiuji Y. Coghill R.C. Patel T.S. et al.Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.Br J Dermatol. 2009; 161: 1072-1080Crossref PubMed Scopus (120) Google Scholar; Papoiu et al., 2014Papoiu A.D. Emerson N.M. Patel T.S. et al.Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease.J Neurophysiol. 2014; 112: 1729-1738Crossref PubMed Scopus (63) Google Scholar). Itch stimulation triggers a complex cerebral response manifested in multiple cortical and subcortical regions that process sensory-discriminative, cognitive, affective, and memory-related dimensions of itch. Projected to the cortex by ventrobasal and posterior thalamic nuclei (Davidson et al., 2012Davidson S. Zhang X. Khasabov S.G. et al.Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate.J Neurophysiol. 2012; 108: 1711-1723Crossref PubMed Scopus (98) Google Scholar), itch registers in the primary and secondary somatosensory areas (S1 and S2) and engages associative parietal regions of the supramarginal, angular gyri, and precuneus. Itch stimulation activates insula, a salience and interoceptive center, and claustrum, a fast stimuli detector and multisensory integrator. The highly charged emotional aspect of itch translates into the activation of deep-seated areas of the cingulate cortex, amygdala, and hippocampus, situated along the Papez circuit (Papez, 1937Papez J.W. A proposed mechanism of emotion.J Neuropsychiatry Clin Neurosci. 1937; 7: 103-112Google Scholar). Itch is a primary sensation that is not easily suppressible, which explains why many forms of itch, and chronic pruritus in particular, remain a clinical challenge. From a therapeutic perspective, the crucial question is which areas are involved in the formation of itch sensation, and among them which could be amenable to medical intervention? In previous neuroimaging studies, clues have been sought to decipher a central mechanism for itch inhibition, using various interventions such as scratching, acupuncture, or thermal modulation (Mochizuki et al., 2003Mochizuki H. Tashiro M. Kano M. et al.Imaging of central itch modulation in the human brain using positron emission tomography.Pain. 2003; 105: 339-346Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar; Yosipovitch et al., 2008Yosipovitch G. Ishiuji Y. Patel T.S. et al.The brain processing of scratching.J Invest Dermatol. 2008; 128: 1806-1811Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar; Vierow et al., 2009Vierow V. Fukuoka M. Ikoma A. et al.Cerebral representation of the relief of itch by scratching.J Neurophysiol. 2009; 102: 3216-3224Crossref PubMed Scopus (47) Google Scholar; Pfab et al., 2010Pfab F. Valet M. Sprenger T. et al.Temperature modulated histamine-itch in lesional and nonlesional skin in atopic eczema - a combined psychophysical and neuroimaging study.Allergy. 2010; 65: 84-94Crossref PubMed Scopus (55) Google Scholar; Papoiu et al., 2013Papoiu A.D.P. Nattkemper L.A. Sanders K.M. et al.Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching.PLoS One. 2013; 8: e82389Crossref PubMed Scopus (83) Google Scholar; Napadow et al., 2014Napadow V. Li A. Loggia M.L. et al.The brain circuitry mediating antipruritic effects of acupuncture.Cereb Cortex. 2014; 24: 873-882Crossref PubMed Scopus (61) Google Scholar). On the basis of the findings of an fMRI study of active scratching, we proposed that the reward-related areas in the midbrain and ventral striatum encode not only the pleasurable aspect of scratching but may hold the key to effectively mediate itch relief (Papoiu et al., 2013Papoiu A.D.P. Nattkemper L.A. Sanders K.M. et al.Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching.PLoS One. 2013; 8: e82389Crossref PubMed Scopus (83) Google Scholar). This hypothesis is in analogy with the concept of pain and pleasure sharing a dual, but common, pathway (Leknes and Tracey, 2008Leknes S. Tracey I. A common neurobiology for pain and pleasure.Nature Rev Neurosci. 2008; 9: 314-320Crossref PubMed Scopus (504) Google Scholar). As reward-related areas express high levels of opioid receptors, an alternative experimental approach is to stimulate them by pharmacological means. The interaction of opioid signaling pathways with itch transduction mechanisms is a topic under active investigation (Kardon et al., 2014Kardon A.P. Polgár E. Hachisuka J. et al.Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.Neuron. 2014; 82: 573-586Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). In this study, we used butorphanol, a mixed-action opioid with a pronounced κ receptor affinity, to study the mechanism underlying its antipruritic action. Butorphanol is FDA approved as an analgesic and is available as a nasal spray or an injectable formulation. Intranasal butorphanol has been used successfully to treat severe cases of chronic pruritus (Dawn and Yosipovitch, 2006Dawn A.G. Yosipovitch G. Butorphanol for treatment of intractable pruritus.J Am Acad Dermatol. 2006; 54: 527-531Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar), and administered epidurally, butorphanol blocks the itch induced by the epidural injection of morphine (Yokoyama et al., 2009Yokoyama Y. Yokoyama T. Nagao Y. et al.Treatment of epidural morphine induced pruritus with butorphanol.Masui. 2009; 58: 178-182PubMed Google Scholar). Histamine and cowhage can be used experimentally in humans to induce itch sensations that are transmitted via distinct peripheral and spinothalamic pathways, which synapse in subtly distinct thalamic nuclei (Davidson et al., 2007Davidson S. Zhang X. Yoon C.H. et al.The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons.J Neurosci. 2007; 27: 10007-10014Crossref PubMed Scopus (208) Google Scholar, Davidson et al., 2012Davidson S. Zhang X. Khasabov S.G. et al.Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate.J Neurophysiol. 2012; 108: 1711-1723Crossref PubMed Scopus (98) Google Scholar). Significant differences in their cortical processing have also been described (Papoiu et al., 2012Papoiu A.D.P. Coghill R.C. Kraft R.A. et al.A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar). Although histamine is the classical experimental pruritogen, the nonhistaminergic protease-activated receptor 2-mediated cowhage itch resembles more closely chronic pruritus of pathological origin. Previous studies have implicated the protease-activated receptor 2 itch pathway in atopic eczema (Steinhoff et al., 2003Steinhoff M. Neisius U. Ikoma A. et al.Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.J Neurosci. 2003; 23: 6176-6180Crossref PubMed Google Scholar) and stressed the lack of therapeutic efficacy of antihistamines in chronic pruritus. Therefore, it is of significant interest to investigate whether butorphanol has a differential effect in relieving these two forms of itch. In this study, we have used fMRI to explore the underlying mechanism of butorphanol’s antipruritic action. Our aim was to identify the key regions in the brain that mediate the inhibition of itch. Butorphanol completely suppressed the itch induced experimentally with histamine (P<0.001), whereas it only reduced the intensity of cowhage itch by approximately 35% (P<0.001; paired t-tests, two-tails, Bonferroni corrected for multiple comparisons; see Figure 1). Butorphanol did not alter sensitivity to heat pain or the heat-pain–associated unpleasantness. Therefore, at a 1 mg dose it appeared that the mixed-action opioid exerted a differential effect on these 3 sensory modalities. Butorphanol induced a significant deactivation of the claustrum, putamen, and anterior and posterior insulae (Figure 2a, in blue; Table 1), which were activated during itch processing by histamine and cowhage. The deactivating effect of butorphanol appeared to overlap to a substantial extent with the areas activated by histamine itch in the contralateral insula and claustrum (in red, Figure 2b) but did not fully overlap (ie counter) the responses evoked by cowhage at the ipsilateral sites (in green, Figure 2c). Butorphanol induced significant activations in the midbrain, in areas consistent with the location of VTA, raphé nucleus, substantia nigra, red nucleus, and periaqueductal gray matter (PAG), as well as cerebellum, precuneus, and thalamus, when analyzed in contrast to the placebo (Figure 3, Table 1).Table 1(A) The main effects of intranasal butorphanol on cerebral perfusion, analyzed in contrast with a placebo; (B) principal areas mediating the antipruritic action of butorphanol on histamine itch, whose activation paralleled itch suppression; (C) results of GLM regression analysis identify deactivation areas correlated with the attenuation of cowhage itch by butorphanol (inhibited approximately 35%)Brain areaxyzZ-scoreA1. Significant activations induced by butorphanol in comparison with placebo Midbrain VTA4-22-142.786-20-182.90 Red nucleus6-20102.31 Sb. nigra14-16-102.91 Dorsal nucleus of raphé2-24-162.55 PAG8-26-42.53 Cerebellum (posterior lobe, uvula)8-66-362.76 Semilunar lobule34-66-442.86 Posterior lobe (cerebellar tonsil)18-46-442.59 Precuneus (BA31)-14-74323.28-4-74522.93 Cuneus-4-84263.44 Thalamus (MDNc)4-1862.706-1842.76A2. Significant deactivations induced by butorphanol Claustrum (L)-36-6-42.87-38-10-43.01-32-1082.51-32-10102.44-32-682.81-3018-63.28 Claustrum (R)321843.01302042.773416-62.86 Anterior insula-42-4-42.45-381842.68-3816-83.84-3814-103.72-3616-63.41 Posterior insula42-2223.01-38-2-42.96 Putamen261042.3922842.36-30-443.71-201842.98-181043.18B. Areas significantly activated during the suppression of histamine itch by butorphanol Nucleus accumbens (L)-108-83.01-108-103.16 Nucleus accumbens (R)66-62.4388-42.31 Medial nucleus of septum28-43.0221003.27210-22.5728-23.08 Nuclei of the diagonal band of Broca410-62.3546-62.5526-82.5328-62.99-68-183.76 Basal nucleus of Meynert-1610-162.50-1810-182.42-1410-182.66 Septal area of ACC (subgenual ACC; BA 25)218-63.05218-142.92C. Deactivation areas significantly correlated with the reduction in cowhage itch S1-34-32583.26 Insula38-6-122.31 Claustrum38-8-102.66 Midbrain (sb. nigra)12-22-123.04 Midbrain (VTA)2-20-103.212-20-126.31 Midbrain (red nucleus)-2-22-122.38 Thalamus (medial dorsal nucleus)-4-1822.83 Pulvinar-22-2642.92 PCC-2-18384.83 Uncus-28-12-324.92 Hippocampus-30-12-306.10 Parahippocampus34-12-224.79 Amygdala-16-12-163.31 Cerebellum Culmen-10-50-224.81 Dentate gyrus18-58-224.87 Declive20-76-224.14 Fusiform gyrus48-50-103.00Abbreviations: ACC, anterior cingulate cortex; GLM, general linear model; PAG, periaqueductal gray matter; PCC, posterior cingulated cortex.Montreal Neurological Institute standard space coordinates. Open table in a new tab Figure 3The brain activations induced by butorphanol, analyzed in comparison with placebo, were found in the midbrain: ventral tegmental area (VTA), periaqueductal gray (PAG), raphé nucleus; in the thalamus, precuneus, and cerebellum. x, y, z—Montreal Neurological Institute (MNI) standard space coordinates.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Abbreviations: ACC, anterior cingulate cortex; GLM, general linear model; PAG, periaqueductal gray matter; PCC, posterior cingulated cortex. Montreal Neurological Institute standard space coordinates. To identify the key brain areas involved in the mediation of the antipruritic effect of butorphanol, we have implemented a study design that allowed us to construct a stepwise contrast between active and control states, when itch was induced in the presence of the drug versus placebo (see Materials and Methods section). This global analysis (performed for the whole-brain) revealed that nucleus accumbens, septal nuclei, and the adjacent septal area of the anterior cingulate cortex were significantly activated during the inhibition of histamine itch (Figure 4, Table 1). These results suggest that suppression of histamine itch was significantly mediated by the activation of these formations. These results were not found in identical contrasts run for the effect of butorphanol on cowhage itch or heat pain (which did not yield significant results). As butorphanol was able to attenuate cowhage itch intensity by 35%, we were interested in investigating whether significant effects in brain perfusion were correlated with the reduction in itch, comparing cowhage itch+drug versus cowhage+placebo conditions. Differences in cerebral perfusion observed for cowhage itch stimulation after butorphanol versus placebo in S1, insula, thalamus, ventral tegmental area (VTA), posterior cingulate cortex (PCC), cerebellum, and hippocampus were significantly correlated with reduction in itch (Table 1, Supplementary Figure S1 online), consistent with a mechanism of butorphanol-induced deactivation. These areas were notably different from the ones identified during the inhibition of histamine itch, which suggests that the inhibition of these 2 itch modalities engages different cerebral networks. Download .pdf (.17 MB) Help with pdf files Supplementary Information In this study, we used ASL fMRI and experimental itch induction to investigate the changes in cerebral perfusion occurring under the effect of butorphanol. This pharmacological fMRI study enabled us to trace meaningful perfusion changes underlying the antipruritic action of this drug in the brain. Because of the particular design of our study, contrast analyses enabled us to identify significant cerebral targets of the drug and to pinpoint key areas engaged during the suppression of histamine itch. In order to characterize the effect of butorphanol on cerebral activity, we have analyzed the changes in cerebral blood perfusion patterns elicited by this opioid drug in contrast with a placebo. Butorphanol significantly and extensively deactivated the claustrum, putamen, and insula, areas previously described to be activated during itch processing. The brain activations induced by butorphanol implicated the midbrain (VTA, red nucleus, and PAG), cerebellum, and precuneus. Interestingly, we recently discovered these structures to be associated with itch relief and pleasurability provided by self-scratching (Papoiu et al., 2013Papoiu A.D.P. Nattkemper L.A. Sanders K.M. et al.Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching.PLoS One. 2013; 8: e82389Crossref PubMed Scopus (83) Google Scholar). The extensive deactivations induced in a contiguous area lying between the putamen and insula, bilaterally, along several coronal planes from z=12 to z=-8 (Montreal Neurological Institute space coordinates), strikingly coincide with the anatomical location of the claustrum. Claustrum is a thin gray matter structure, which expresses a very high density of κ-opioid receptors (“++++”), as shown by in situ hybridization studies in humans and labeling studies in primates (Peckys and Landwehrmeyer, 1999Peckys D. Landwehrmeyer G.B. Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study.Neuroscience. 1999; 88: 1093-1135Crossref PubMed Scopus (210) Google Scholar; Sim-Selley et al., 1999Sim-Selley L.J. Daunais J.B. Porrino L.J. et al.Mu and kappa1 opioid-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding in cynomolgus monkey brain.Neuroscience. 1999; 94: 651-662Crossref PubMed Scopus (45) Google Scholar). The significant deactivation we found is also consistent with the mechanism of action of opioids, which induce neuronal inhibition by hyperpolarization. Therefore, the present results tracing the effects of butorphanol by fMRI are in agreement with the structural data on the expression of its target receptors in the human brain and with its known molecular mechanism. These findings support our previous observation that claustrum has a significant role in itch processing (Papoiu et al., 2012Papoiu A.D.P. Coghill R.C. Kraft R.A. et al.A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar). The high-density pattern of expression of κ-opioid receptors in the claustrum is consistent across species, in primates and rodents (Meng et al., 1993Meng F. Xie G.X. Thompson R.C. et al.Cloning and pharmacological characterization of a rat kappa opioid receptor.Proc Natl Acad Sci USA. 1993; 90: 9954-9958Crossref PubMed Scopus (386) Google Scholar; Mansour et al., 1994Mansour A. Fox C.A. Burke S. et al.Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study.J Comp Neurol. 1994; 350: 412-438Crossref PubMed Scopus (716) Google Scholar). The complete inhibition of histamine itch by butorphanol was paralleled by significant activations, which mapped to nucleus accumbens, septal nuclei, slightly extending laterally to the basal nucleus of Meynert, and to the adjacent septal area of subgenual anterior cingulate cortex (BA 25), which suggests that the antipruritic action of butorphanol is mediated by these formations. The identification of structures within the human brain underlying the antipruritic effect of an opioid that showed clinical efficacy is to our knowledge previously unreported. Nucleus accumbens has been previously described to have a significant role in mediating opioid- and nociceptive stimulus–induced analgesia. In humans, NAc expresses a high density of μ, κ, and δ opioid receptors at comparable levels (Peckys and Landwehrmeyer, 1999Peckys D. Landwehrmeyer G.B. Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study.Neuroscience. 1999; 88: 1093-1135Crossref PubMed Scopus (210) Google Scholar). A complex interplay between μ/δ and κ receptors has been described in the modulation of antinociception mediated by nucleus accumbens (Schmidt et al., 2002Schmidt B.L. Tambeli C.H. Levine J.D. et al.μ/δ Cooperativity and opposing κ-opioid effects in nucleus accumbens-mediated antinociception in the rat.Eur J Neurosci. 2002; 15: 861-868Crossref PubMed Scopus (58) Google Scholar), and dopamine has been proposed as the critical mediator in accumbens-mediated antinociception (Altier and Stewart, 1998Altier N. Stewart J. Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine.J Pharmacol Exp Ther. 1998; 285: 208-215PubMed Google Scholar). In nucleus accumbens, μ-receptor activation leads to dopamine release (Yokoo et al., 1994Yokoo H. Yamada S. Yoshida M. et al.Effect of opioid peptides on dopamine release from nucleus accumbens after repeated treatment with methamphetamine.Eur J Pharmacol. 1994; 256: 335-338Crossref PubMed Scopus (22) Google Scholar), whereas κ-receptor activation decreases dopamine release (Bals-Kubik et al., 1993Bals-Kubik R. Ableitner A. Herz A. et al.Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.J Pharmacol Exp Ther. 1993; 264: 489-495PubMed Google Scholar). Thus, a tempting hypothesis is that κ-mediated antipruritic action depends on decreasing dopamine release in nucleus accumbens. However, kappa-opioid-mediated activation also decreases the release of glutamate and GABA from nucleus accumbens, using different mechanisms (Hjelmstad and Fields, 2003Hjelmstad G.O. Fields H.L. Kappa opioid receptor activation in the nucleus accumbens inhibits glutamate and GABA release through different mechanisms.J Neurophysiol. 2003; 89: 2389-2395Crossref PubMed Scopus (92) Google Scholar). The κ opioid receptor sits on the presynaptic side of the excitatory synapses and dendrites of GABA-ergic spiny neurons of the nucleus accumbens shell and could be regulated by glutamatergic inputs from the prefrontal cortex, amygdala, or hippocampus (Schmidt et al., 2002Schmidt B.L. Tambeli C.H. Levine J.D. et al.μ/δ Cooperativity and opposing κ-opioid effects in nucleus accumbens-mediated antinociception in the rat.Eur J Neurosci. 2002; 15: 861-868Crossref PubMed Scopus (58) Google Scholar). Of note, the septal area is directly interconnected with the hippocampus and amygdala. Septal nuclei are discrete gray matter structures that include the medial nucleus of septum and the diagonal band of Broca, mostly composed of cholinergic, GABA-ergic, and glutamatergic neurons. Notably, septal nuclei drive the hippocampal theta rhythm and are highly synchronized with hippocampal activity (Petsche et al., 1962Petsche H. Stumpf C. Gogolák G. The significance of the rabbit's septum as a relay station between midbrain and the hippocampus: I. The control of hippocampus arousal activity by the septum cells.Electroencephalogr Clin Neurophysiol. 1962; 14: 202-211Abstract Full Text PDF PubMed Scopus (507) Google Scholar; Vertes and Kocsis, 1997Vertes R.P. Kocsis B. Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus.Neuroscience. 1997; 81: 893-926Crossref PubMed Scopus (644) Google Scholar; Hangya et al., 2009Hangya B. Borhegyi Z. Szilágyi N. et al.GABAergic neurons of the medial septum lead the hippocampal network during theta activity.J Neurosci. 2009; 29: 8094-8102Crossref PubMed Scopus (216) Google Scholar). An interesting observation that could be relevant to itch processing is that sensory stimulation resets the pace of theta oscillations in the septal nuclei (Buzsáki et al., 1979Buzsáki G. Grastyán E. Tveritskaya I.N. et al.Hippocampal evoked potentials and EEG changes during classical conditioning in the rat.Electroencephalogr Clin Neurophysiol. 1979; 47: 64-74Abstract Full Text PDF PubMed Scopus (48) Google Scholar). Neurons operating in phase-lock with the hippocampal theta oscillation were found in the ventral tegmentum and dorsal raphé nucleus (Bland, 1986Bland B.H. Physiology and pharmacology of hippocampal formation theta rhythms.Prog Neurobiol. 1986; 26: 1-54Crossref PubMed Scopus (853) Google Scholar). These structures were implicated in the relief of itch induced by self-scratching (Papoiu et al., 2013Papoiu A.D.P. Nattkemper L.A. Sanders K.M. et al.Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching.PLoS One. 2013; 8: e82389Crossref PubMed Scopus (83) Google Scholar) and were activated by butorphanol in this study (Figure 3). The medial septal region has been proposed to function as a node for the ascending brainstem pathways, sending inputs to the posterior cingulate, enthorinal cortex, and hippocampus (Bland, 2000Bland B.H. The medial septum: node of ascending brainstem hippocampal synchronizing pathways.The Behavioral Neuroscience of the Septal Region. 2000; vol. 6: 115-145Crossref Google Scholar; Bland and Oddie, 2001Bland B.H. Oddie S.D. Theta band oscillation and synchrony in the hippocampal formation and associated structures: the case for its role in sensorimotor integration.Behav Brain Res. 2001; 127: 119-136Crossref PubMed Scopus (408) Google Scholar). Recent studies have implicated the medial septal nucleus in general anesthesia (Ma et al., 2002Ma J. Shen B. Stewart L.S. et al.The septohippocampal system participates in general anesthesia.J Neurosci. 2002; 22: RC200PubMed Google Scholar; Leung et al., 2013Leung L.S. Ma J. Shen B. et al.Medial septal lesion enhances general anesthesia response.Exp Neurol. 2013; 247: 419-428Crossref PubMed Scopus (17) Google Scholar, Tai et al., 2014Tai S.K. Ma J. Leung L.S. Medial septal cholinergic neurons modulate isoflurane anesthesia.Anesthesiology. 2014; 120: 392-402Crossref PubMed Scopus (17) Google Scholar). The septal area has also been associated with analgesia induced by acupuncture (Xiong and Zheng, 1990Xiong K. Zheng P. The effect of the septal area in acupuncture analgesia.Zhen Ci Yan Jiu. 1990; 15: 1-5PubMed Google Scholar; Zhao, 2008Zhao Z.Q. Neural mechanism underlying acupuncture analgesia.Prog Neurobiol. 2008; 85: 355-375Crossref PubMed Scopus (680) Google Scholar). A classical electrophysiological experiment using implanted electrodes linked septal nuclei with reward processing and highly pleasurable experiences (Olds and Milner, 1954Olds J. Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain.J Comp Physiol Psychol. 1954; 47: 419-427Crossref PubMed Scopus (1801) Google Scholar). The septal area of anterior cingulate cortex is connected with nucleus accumb" @default.
• W2015480400 created "2016-06-24" @default.
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• W2015480400 creator A5032105584 @default.
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• W2015480400 date "2015-02-01" @default.
• W2015480400 modified "2023-10-12" @default.
• W2015480400 title "Butorphanol Suppression of Histamine Itch Is Mediated by Nucleus Accumbens and Septal Nuclei: A Pharmacological fMRI Study" @default.
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