An ultrastructural study of the projections from the midbrain periaqueductal gray to spinally projecting, serotonin-immunoreactive neurons of the medullary nucleus raphe magnus in the rat

doi:10.1016/0006-8993(88)91638-1

Brain Research

Volume 443, Issues 1–2, 8 March 1988, Pages 383-388

https://doi.org/10.1016/0006-8993(88)91638-1 Get rights and content

Abstract

In this triple-label, electron microscopic study in the rat, a lesion of the midbrain periaqueductal gray (PAG) was made so that the distribution and targets of degenerating PAG terminals could be identified in the medullary nucleus raphe magnus (NRM). Spinally projecting NRM neurons were identified by the retrograde transport of wheat germ agglutinin-horseradish peroxidase from the cervical cord. We also used immunocytochemistry to define the subpopulation of NRM neurons which were serotonin-immunoreactive. We report that both serotonergic and non-serotonergic neurons of the medulla, which project to the spinal cord, receive monosynaptic inputs from the PAG.

References (31)

M.M. Behbehani et al.
Effect of morphine injected in the periaqueductal gray on the activity of single units in nucleus raphe magnus of the rat
Brain Research
(1978)
R.M. Bowker et al.
Origins of serotonergic projections to the spinal cord in rat: an immunocytochemical-retrograde transport study
Brain Research
(1981)
E. Carstens et al.
Serotonergic mediation of descending inhibition from midbrain periaqueductal gray, but not reticular formation of spinal nociceptive transmission in the rat
Pain
(1981)
Z.-F. Cheng et al.
Morphine microinjected into the periaqueductal gray has differential effects on three classes of medullary neurons
Brain Research
(1986)
H.L. Fields et al.
Evidence that raphe-spinal neurons mediate opiate and midbrain stimulation-produced analgesia
Pain
(1978)
H.L. Fields et al.
Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons
Brain Research
(1977)
T. Hökfelt et al.
Immunohistochemical evidence of substance P-like immunoreactivity in some 5-HT-containing neurons in the rat central nervous system
Neuroscience
(1978)
M.B. Llewelyn et al.
Effects of 5-hydroxytryptamine applied into nucleus raphe magnus on nociceptive thresholds and neuronal firing rate
Brain Research
(1983)
D. Menétrey et al.
The distribution of substance P, enkephalin and dynorphin immunoreactive neurons in the medulla of the rat and their contribution to bulbospinal pathways
Neuroscience
(1987)
G.F. Prieto et al.
Nucleus raphe magnus lesions disrupt stimulation-produced analgesia from ventral but not dorsal midbrain areas in the rat
Brain Research
(1983)

M.H.T. Roberts

5-Hydroxytryptamine and antinociception

Neuropharmacology

(1984)

H. Vanegas et al.

Midbrain stimulation inhibits tail-flick only at currents sufficient to excite rostral-medullary neurons

Brain Research

(1984)

T.L. Yaksh et al.

Antagonism by methysergide and cinanserin of the antinociceptive action of morphine administered into the periaqueductal gray

Brain Research

(1976)

I.A. Abols et al.

Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain-medullary interactions

J. Comp. Neurol.

(1981)

J.C. Adams

Technical considerations on the use of horseradish peroxidase as a neuronal marker

Neuroscience

(1977)

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Projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) are known to engage in descending pain modulation, but how the neural substrates of the PAG-RVM projections contribute to neuropathic pain remains largely unknown. In this study, we showed somatostatin-expressing glutamatergic neurons in the lateral/ventrolateral PAG that facilitate mechanical and thermal hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain. We found that these neurons form direct excitatory connections with neurons in the RVM region. Inhibition of this PAG-RVM projection alleviates mechanical and thermal hypersensitivity associated with neuropathy, whereas its activation enhances hypersensitivity in the mice. Thus, our findings revealed that somatostatin neurons within the PAG-RVM axial are crucial for descending pain facilitation and can potentially be exploited as a useful therapeutic target for neuropathic pain.
We report the profound contribution of somatostatin neurons within the PAG-RVM projections to descending pain facilitation underlying neuropathic pain. These results may help to develop central therapeutic strategies for neuropathic pain.
Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation
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Moreover, electric stimulation of the PAG briefly reduced a histamine-evoked discharge recorded from neurons in the dorsal spinal cord of anesthetized animals (Carstens, 1997), pointing to the potential involvement of the PAG in itch processing. The PAG is well known for its critical role in modulating sensory processing (e.g., nociception) at the spinal level via a descending pathway (Basbaum and Fields, 1984; Heinricher et al., 1987; Hohmann et al., 2005; Lakos and Basbaum, 1988; Park et al., 2010), and electrical stimulation of the PAG causes pain inhibition (Liebeskind et al., 1973; Yeung et al., 1977). Furthermore, the PAG is a major brain area involved in morphine analgesia and endogenous pain control (Basbaum and Fields, 1984; Chieng and Christie, 1996; Park et al., 2010; Reynolds, 1969; Taylor and Basbaum, 2003; Yeung et al., 1977).
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.
Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy
2016, Neuropharmacology
Citation Excerpt :
However, the location of supraspinal TRPV1 involved in acetominophen analgesia remains to be clarified. Considering the crucial role of RVM descending serotoninergic pathways in pain control (Lakos and Basbaum, 1988), which account for the antinociceptive drive induced by PAG or RVM stimulation (Aimone et al., 1987; Rivot et al., 1984), it will be important to ascertain the involvement of serotoninergic spinally-projecting RVM neurons in the TRPV1-mediated antinociceptive effects during DNP, inasmuch as RVM serotoninergic neurotransmission was also shown to be altered during diabetes (Morgado et al., 2011). The possible involvement of serotoninergic spinally-projecting RVM neurons should be evaluated by manipulating local TRPV1 receptors and measuring the release of serotonin at the spinal cord.
The involvement of transient receptor vanilloid type-1 (TRPV1) channels in pain modulation by the brain remains understudied. The rostroventromedial medulla (RVM) plays a key role in conveying to the spinal cord pain modulatory influences triggered in higher brain centres, with co-existence of inhibitory (antinociceptive) and facilitatory (pronociceptive) effects. In spite of some reports of TRPV1 expression in the RVM, it remains unknown if endovanilloid signalling plays a direct role in local pain modulation. Here we used a model of diabetic neuropathy, the streptozotocin (STZ)-diabetic rat, to study the role of endovanilloid signalling in RVM-mediated pain modulation during chronic pain. Four weeks after diabetes induction, the levels of TRPV1 mRNA and fatty acid amide hydrolase (FAAH), a crucial enzyme for endovanilloid catabolism, in the RVM of STZ-diabetic rats were higher than control. The RVM of STZ-diabetic rats presented decreased levels of several TRPV1 endogenous ligands, namely anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Administration of capsaicin (a TRPV1 agonist) into the RVM decreased nociceptive behavioural responses in the inflammatory phase of the formalin test (phase 2). These findings suggest that diabetic neuropathy induces plastic changes of RVM endovanilloid signalling, indicating that TRPV1 may be a putative target for pain modulation in this chronic pain condition.
Central Autonomic System
2015, The Rat Nervous System: Fourth Edition
The central autonomic system is defined by the cell groups that receive direct or disynaptically relayed input from the nucleus of the solitary tract, or that contribute projections to autonomic preganglionic neurons or their presynaptic inputs. The cell groups identified by these properties also project extensively among themselves, forming a true network. In this chapter, we identify the cell groups from the medulla and spinal cord through the brainstem, hypothalamus, thalamus, amygdala, and cortex that contribute to the central autonomic system. We then review the connections within the central autonomic network; the pathways that provide visceral sensory input to, and visceral motor output from the network; and the connections of the central autonomic system with cognitive, endocrine, and behavioral systems that must be integrated with autonomic responses. We also consider the neurotransmitters used by this network, and how they contribute to its functions.
Sex differences in connectivity of the subgenual anterior cingulate cortex
2014, Pain
We previously reported that women exhibit greater heat pain adaptation to a prolonged painful stimulus and greater habituation to repeated painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, Bingel et al. (2007) have shown that pain habituation after 8 days of daily pain testing is associated with an increase in pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), suggesting that pain habituation may be mediated via connectivity between the sgACC and the descending pain antinociceptive system. Therefore, we investigated whether women have stronger functional connectivity (FC) and greater structural connectivity (SC) compared to men between the sgACC and the descending antinociceptive system. Our analyses revealed that 1) women exhibited greater FC between the sgACC and the periaqueductal gray (PAG), raphe nucleus, medial thalamus, and anterior midcingulate cortex (aMCC) than men; 2) men had stronger sgACC FC with the anterior insula and temporoparietal junction than women; 3) women and men exhibited comparable SC of the sgACC with the PAG, thalamus, aMCC, anterior insula, and amygdala; and 4) men have stronger sgACC SC with the hypothalamus than women. These data indicate that brain circuitry in women may provide for greater engagement of the descending modulation system mediating pain habituation. In contrast, in men, the salience network may be more engaged, which could support greater sustained attention to pain, thereby preventing pain habituation. Furthermore, the hypothalamus findings suggest a more powerful stress and endorphin-based system at play in men than women.
Presynaptic kainate receptors increase GABAergic neurotransmission in rat periaqueductal gray neurons
2010, European Journal of Pharmacology
Neurons within the periaqueductal gray (PAG) have been implicated in the central regulation of pain signals by affecting the descending inhibitory pathway. Here we report on the functional role of presynaptic kainate receptors within the PAG. Using a conventional whole-cell patch clamp technique, we recorded GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) from mechanically isolated rat PAG neurons in the presence of 300 nM tetrodotoxin and 20 µM dl-2-amino-5-phosphonovaleric acid under voltage-clamp conditions. Kainic acid at a 10 µM concentration significantly increased the frequency of GABAergic mIPSCs without affecting their amplitude, suggesting that kainic acid acts presynaptically to enhance spontaneous GABA release. The kainic acid-induced increase in mIPSC frequency was completely blocked by CNQX, a selective AMPA/kainate receptor antagonist. While neither AMPA nor NMDA affected GABAergic mIPSC frequency, ATPA, a selective agonist of GluR5-containing kainate receptors, increased GABAergic mIPSC frequency in a concentration-dependent manner. The kainic acid-induced increase in mIPSC frequency was completely suppressed either in the presence of 100 µM Cd²⁺, a general voltage-dependent Ca²⁺ channel (VDCC) blocker, or in the Na⁺-free external solution. These results suggest that presynaptic kainate receptors have a low permeability to Ca²⁺, and that their activation elicits a presynaptic depolarization large enough to activate presynaptic VDCCs. Presynaptic kainate receptors on GABAergic nerve terminals appear to modulate GABAergic transmission, and in doing so may play an important role in the regulation of PAG neuron excitability.

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^☆: This work was supported by PHS Grants NS 21445 and 14627.

^∗: Present address: Department of Physiology, Rockefeller University.

¹: We thank Ms. Bonnie Lord for help with the electron microscopy and Ms. Allison Gannon and Simona Ikeda for photographic assistance. We also thank Dr. Jon Levine for help in the preparation of the manuscript.

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Short communicationAn ultrastructural study of the projections from the midbrain periaqueductal gray to spinally projecting, serotonin-immunoreactive neurons of the medullary nucleus raphe magnus in the rat☆

Abstract

Brain Research

Brain Research

Pain

Brain Research

Pain

Brain Research

Neuroscience

Brain Research

Neuroscience

Brain Research

Neuropharmacology

Brain Research

Brain Research

Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain-medullary interactions

J. Comp. Neurol.

Technical considerations on the use of horseradish peroxidase as a neuronal marker

Neuroscience

Short communication
An ultrastructural study of the projections from the midbrain periaqueductal gray to spinally projecting, serotonin-immunoreactive neurons of the medullary nucleus raphe magnus in the rat☆