Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray

Heinricher, Mary M.; Cheng, Zhenfeng; Fields, Howard L.

doi:10.1523/jneurosci.07-01-00271.1987

Cited by 109 publications

(58 citation statements)

References 65 publications

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“…The amygdala has direct projections to the PAG (26), which in turn projects to the RVM (27). PAG and RVM contain "on cells" and "off cells" (28,29). In animals, on cells start firing while off cells stop firing in response to a noxious stimulus.…”

Section: Discussionmentioning

confidence: 99%

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

Wanigasekera

Lee

Rogers

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the μ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the μ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral-ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.functional MRI | functional imaging | endophenotype O pioids are the mainstay of moderate to severe pain management, but there is considerable variation in the analgesic response leading to inadequate analgesia for many patients (1). This variability has been attributed to many factors including the genetic variability of the μ-opioid receptor (MOR)-encoding gene that introduces variability in MOR function and endogenous opioid neurotransmission (2). Endogenous opioid neurotransmission mediates exogenous opioid analgesia (3), increases in response to noxious stimuli reducing the unpleasantness of noxious stimuli (4), enhances the pleasantness of rewarding stimuli (5), and influences the responsiveness of an individual to rewards (6). Therefore, endogenous opioids play a central role not only in mediating exogenous opioid analgesia, but also in endogenous modulation of pain perception and reward processing.Reward is not one simple construct, and there are many different types of reward such as monetary gain, palatable food, mood enhancing drugs, and social reward. An increasingly wellidentified set of brain regions consisting of the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), the ventral striatum, ventral pallidum, and the midbrain tegmentum as well as the prefrontal cortex, amygdala and the hippocampus are differentially involved in processing...

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Section: Discussionmentioning

confidence: 99%

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

Wanigasekera

Lee

Rogers

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Moreover, whereas in several experiments of the current study, OFF cells might control ON cell burst, this does not hold true for the 2.5 nmol/rat dose of URB597 where ON cell burst occurred simultaneously with or even preceded OFF cell pause, thus indicating that cessation of OFF cell firing was not required for the increase of the ON cell firing. Thus, the involvement of different PAG outputs modulating distinct RVM cells should not be excluded (Heinricher et al, 1987) (Table 1). …”

Section: Downloaded Frommentioning

confidence: 99%

Elevation of Endocannabinoid Levels in the Ventrolateral Periaqueductal Grey through Inhibition of Fatty Acid Amide Hydrolase Affects Descending Nociceptive Pathways via Both Cannabinoid Receptor Type 1 and Transient Receptor Potential Vanilloid Type-1 Receptors

Maione

Bisogno

Novellis

et al. 2005

J Pharmacol Exp Ther

264

242

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In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB 1 ) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3Ј-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB 1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB 1 receptors and only CB 1 receptors, respectively. The TRPV1-mediated antinociception and CB 1 -mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB 1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB 1 -mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB 1 or TRPV1 receptors in healthy rats.Two G-protein-coupled receptors for Cannabis psychotropic component ⌬ 9 -tetrahydrocannabinol have been cloned to date (Matsuda et al., 1990;Munro et al., 1993) and are implicated in the control of nociception under both physiological and pathological conditions (for review, see IversenThis work was partly supported by the VolkswagenStiftung (to V.D.M.) and Progretti di Ricerca di Rilevante Interesse Nazionale 2003 (Ministero dell'Istruzione dell'Università e della Ricerca, Rome, Italy) (to S.M.).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.093286.ABBREVIATIONS: CB 1 , cannabinoid receptor type 1; CB 2 , cannabinoid receptor type 2; ACSF, artificial cerebrospinal fluid; 2-AG, 2-arachidonoylglycerol; FAAH, fatty acid amide hydrolase; % MPE, percentage of the maximal possible effect; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; TRPV1, transient receptor potential vanilloid type-1; ca...

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“…In addition to vocalization, activation of the lateral or ventrolateral regions of PAG has long been associated with an increase in sensory thresholds (Reynolds, 1969;Heinricher et al, 1987;Budai et al, 1998). In many mammalian species, changes in nociceptive thresholds, particularly in the female, are essential for successful reproduction to take place.…”

Section: Functional Implications Of a Steroidresponsive Mpo3 Pag3npgimentioning

confidence: 99%

Distribution of gonadal steroid receptor–containing neurons in the preoptic–periaqueductal gray–brainstem pathway: A potential circuit for the initiation of male sexual behavior

Murphy

Hoffman

2001

J of Comparative Neurology

120

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The present study used anterograde and retrograde tract tracing techniques to examine the organization of the medial preoptic-periaqueductal gray-nucleus paragigantocellularis pathway in the male rat. The location of neurons containing estrogen (alpha subtype; ER alpha) and androgen receptors (AR) were also examined. We report here that injection of the anterograde tracer biotinylated dextran amine (BDA) into the medial preoptic (MPO) produced dense labeling within the periaqueductal gray (PAG); anterogradely labeled fibers terminated in close juxtaposition to neurons retrogradely labeled from the nucleus paragigantocellularis (nPGi). Dual immunostaining for Fluoro-Gold (FG) and ER alpha or FG and AR showed that over one-third of MPO efferents to the PAG contain receptors for either estrogen or androgen. In addition, approximately 50% of PAG neurons retrogradely labeled from the nPGi were immunoreactive for either ER alpha or AR. These results are the first to establish an MPO-->PAG-->nPGi circuit and further indicate that gonadal steroids can influence neuronal synaptic activity within these sites. We reported previously that nPGi reticulospinal neurons terminate preferentially within the motoneuronal pools of the lumbosacral spinal cord that innervate the pelvic viscera. Together, we propose that the MPO-->PAG-->nPGi circuit forms the final common pathway whereby MPO neural output results in the initiation and maintenance of male copulatory reflexes.

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Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray

Cited by 109 publications

References 65 publications

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects

Elevation of Endocannabinoid Levels in the Ventrolateral Periaqueductal Grey through Inhibition of Fatty Acid Amide Hydrolase Affects Descending Nociceptive Pathways via Both Cannabinoid Receptor Type 1 and Transient Receptor Potential Vanilloid Type-1 Receptors

Distribution of gonadal steroid receptor–containing neurons in the preoptic–periaqueductal gray–brainstem pathway: A potential circuit for the initiation of male sexual behavior

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