Endomorphin‐2‐immunoreactive fibers selectively appose serotonergic neuronal somata in the rostral ventral medial medulla

Gu, Ming; Wessendorf, Martin W.

doi:10.1002/cne.21343

Cited by 19 publications

(20 citation statements)

References 53 publications

(83 reference statements)

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“…Intra‐RVM tracer‐injected animals were used for in vitro slice experiments at 1–2 weeks post‐surgery. The core of the tracer injections was examined post hoc to verify correct placement within the RVM (see Figure a inset), which was defined as a triangular region bordered rostrocaudally by the trapezoid body and inferior olive, ventrally by the pyramidal tract and laterally by the extent of the pyramidal tract (Gu & Wessendorf, ).…”

Section: Methodsmentioning

confidence: 99%

Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway

Lau

Winters

Vaughan

2020

British J Pharmacology

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Background and Purpose: The midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear. Experimental Approach: Patch clamp recordings in voltage-and current-clamp mode were made from acutely prepared PAG slices from animals that received retrograde tracer injections into the RVM. Key Results: The μ-agonist DAMGO reduced GABAergic evoked inhibitory postsynaptic currents (IPSCs) in retro-labelled, RVM-projecting neurons to a greater extent than in unlabelled neurons. The κ-opioid agonist U69593 reduced evoked IPSCs to a similar extent in both neuronal groups, while the δ-opioid agonist deltorphin-II was without effect. DAMGO and U69593 both produced a reduction in the rate, but not amplitude of spontaneous miniature IPSCs and asynchronous evoked IPSCs in retrolabelled neurons. DAMGO and U69593 also suppressed glutamatergic EPSCs in retro-labelled and unlabelled neurons. The DAMGO inhibition of evoked EPSCs, however, was less than that for evoked IPSCs in retro-labelled, but not unlabelled neurons. In current clamp, DAMGO produced a depolarizing increase in evoked postsynaptic potentials in retro-labelled neurons, but directly inhibited unlabelled neurons. Conclusion and Implications: These findings suggest that μ-opioids activate the descending analgesic pathway from the midbrain PAG by a combination of presynaptic disinhibition of RVM-projecting neurons and postsynaptic inhibition of presumptive interneurons.

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Section: Methodsmentioning

confidence: 99%

Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway

Lau

Winters

Vaughan

2020

British J Pharmacology

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“…The lateral borders of the rectangle were located at the middle distance between the lateral edge of the pyramid and the most medial edge of the facial nucleus (Figure 1). The planar rectangular shape of the area used for stereological analyses differed from the triangular shape of the RVM area, which includes primarily the nucleus raphe magnus, that was used in earlier studies (Gu and Wessendorf, 2007; Leong et al, 2011). This rectangular area of the RVM, as used earlier (Parra et al, 2002; Hurley et al, 2003), ensured quantification of NK-1R neurons not only in nucleus raphe magnus but also in nuclei gigantocellularis pars alpha, and lateral paragigantocellular, which are components of the RVM (Millan, 2002).…”

Section: Methodsmentioning

confidence: 99%

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

Khasabov

Simone

2013

Neuroscience

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It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1R) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar9, Met(O2)11-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1 μM) or an equal volume of 1 μM of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21–24 days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5–28 days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund’s adjuvant (CFA) (prolonged hyperalgesia). The proportion of NK-1R-labeled neurons in the RVM was 8.8 ± 1.3% in naïve rats and 8.1 ± 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.

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“…The RVM was defined as an isosceles triangle that lies at the level of the facial nucleus with a base having a width equal to that of the combined pyramidal tracts, and its height equal to half the width of the base (Figure 1) (Gu and Wessendorf, 2007). The RVM extended from the rostral end of inferior olive to the caudal end of the trapezoid body.…”

Section: Methodsmentioning

confidence: 99%

“…both ipsilateral and contralateral to the surgery). Systematic random sampling and unbiased stereological methods were used for quantification as described previously (Gu and Wessendorf, 2007). Five RVM sections (each 50 μm thick) per animal were sampled; the first section sampled was selected randomly.…”

Section: Methodsmentioning

confidence: 99%

Neuronal Loss in the Rostral Ventromedial Medulla in a Rat Model of Neuropathic Pain

Leong¹,

Gu²,

Speltz-Paiz³

et al. 2011

J. Neurosci.

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Cell death has been reported in the CNS in models of neuropathic pain (Sugimoto et al., 1990; Whiteside and Munglani, 2001; Scholz et al., 2005; Fuccio et al., 2009). In our present study, we examined the effects of spinal nerve ligation (SNL) on the number of neurons in the rostral ventromedial medulla (RVM), a brain stem region involved in modulation of nociception. In rats receiving SNL, we found that the number of RVM neurons decreased by 23% in the side ipsilateral to the surgery. The loss of RVM neurons was also associated with a bilateral increase in the number of glia as well as bilateral activation of both astrocytes and microglia. Administration of tauroursodeoxycholic acid (TUDCA), which reportedly inhibits apoptosis, significantly reduced the loss of neurons, the increase in glia, and the mechanical hypersensitivity induced by SNL. Among RVM neurons, we found that serotonergic (5-HT) neurons decreased by 35% ipsilateral to SNL. Consistent with these findings, the density of 5-HT-immunoreactive varicosities in the superficial dorsal horn of the spinal cord was 15–30% lower, ipsilateral to SNL. To test the function of the remaining 5-HT neurons, we administered the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Interestingly, after 5,7-DHT, mechanical withdrawal thresholds increased significantly. We conclude that nerve injury induces death of antinociceptive RVM neurons that can be reduced or abolished by TUDCA. We propose that the loss of RVM neurons shifts the balance of descending control from pain inhibition to pain facilitation.

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Endomorphin‐2‐immunoreactive fibers selectively appose serotonergic neuronal somata in the rostral ventral medial medulla

Cited by 19 publications

References 53 publications

Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway

Opioid presynaptic disinhibition of the midbrain periaqueductal grey descending analgesic pathway

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

Neuronal Loss in the Rostral Ventromedial Medulla in a Rat Model of Neuropathic Pain

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