Changes in [125I]hCGRP binding in rat spinal cord in an experimental model of acute, peripheral inflammation

Galeazza, M.T.; Stucky, Cheryl L.; Seybold, Virginia S.

doi:10.1016/0006-8993(92)91700-o

Cited by 24 publications

(6 citation statements)

References 49 publications

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“…While this possibility needs further clarification, the present result revealed that in adjuvant-induced arthritic rats, a decrease in CGRP and NKl receptor binding sites is associated with concomitant increases in their respective immunoreactive peptides. Furthermore, in conjunction with earlier reports, the present data support the current notion that [1251]hCGRP~ (Galeazza et al, 1992) and [1251]BH-substance P/NKl (Mantyh and Hunt, 1985;Yashpal et al, 1991) receptors are not present on the primary afferent terminals in the dorsal horn, but rather are possibly located postsynaptically.…”

Section: Regulation Of Peptide Receptor Binding Sitessupporting

confidence: 92%

“…Consistent with earlier reports (Mantyh and Hunt, 1985;Yashpal et al, 1991;Galeazza et al, 1992), high amounts of ['251]hCGRPa and [12SI]BH-substance P/NK1 binding sites in control rats were noted in the deeper and superficial layers of the dorsal horn respectively. The distribution of [ 1251]BH-substance P/NK1 receptor binding sites, in general, correlates well with the localization of substance P-immunoreactive fibres.…”

Section: Regulation Of Peptide Receptor Binding Sitessupporting

confidence: 92%

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Altered Calcitonin Gene‐related Peptide, Substance P and Enkephalin Immunoreactivities and Receptor Binding Sites in the Dorsal Spinal Cord of the Polyarthritic Rat

Kar

Rees

Quirion

1994

Eur J of Neuroscience

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The dorsal horn of the spinal cord, which forms the locus of first synapses in pain pathways, is an important site of interaction between calcitonin gene-related peptide (CGRP), substance P and enkephalin--the neuropeptides considered to be especially involved in the regulation of pain perception. Since adjuvant-induced arthritic rats provide a suitable model for peripheral inflammation and hyperalgesia, the possible alterations of immunoreactive CGRP, substance P and enkephalin as well as the binding sites for [125I]hCGRP alpha, [125I]substance P/neurokinin-1, (NK1) and [125I]FK-33-824/mu-opioid receptors were studied in the dorsal horn of the spinal cord receiving projections from the inflamed limbs. In arthritic rats compared to control animals, a bilateral increase in CGRP- and substance P-immunoreactive fibres and the presence of enkephalin-immunoreactive cell bodies were noted in the dorsal horn of the spinal cord. As for receptors, while a significant decrease in [125I]hCGRP alpha and [125I]substance P/NK1 binding sites was observed in selective layers, no measurable alteration in [125I]FK-33-824/mu-opioid binding sites was noted in any regions of the arthritic rat dorsal horn compared to the unaffected control rats. Following unilateral section of the peripheral nerve prior to induction of arthritis, CGRP- and substance P-immunoreactive fibres were markedly depleted and no enkephalin-positive neurons were observed in the ipsilateral dorsal horn. Analysis of receptor binding sites in denervated arthritic rats, however, exhibited differential responses, i.e. a significant increase in [125I]hCGRP alpha, a marked decrease in [125I]FK-33-824/mu-opioid and apparently no alteration in [125I]substance P/NK1 receptor binding sites were observed in the ipsilateral dorsal horn compared to the intact contralateral side. These results taken together provide anatomical evidence for a concerted role of these peptides in the regulation of adjuvant-induced hyperalgesia accompanying peripheral inflammation.

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Section: Regulation Of Peptide Receptor Binding Sitessupporting

confidence: 92%

Section: Regulation Of Peptide Receptor Binding Sitessupporting

confidence: 92%

Altered Calcitonin Gene‐related Peptide, Substance P and Enkephalin Immunoreactivities and Receptor Binding Sites in the Dorsal Spinal Cord of the Polyarthritic Rat

Kar

Rees

Quirion

1994

Eur J of Neuroscience

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“…RAMP1 is regulated by a number of stimuli 26. It is especially intriguing that peripheral inflammation can lead to changes in CGRP binding sites in the dorsal horn of the spinal cord 22,29. Given the growing evidence for a causal role for CGRP in migraine and the likelihood of neurogenic inflammation during migraine, it seems likely that the enhanced mechanical allodynia seen with this mouse model may reflect a role for CGRP and RAMP1 in central sensitization in migraine.…”

Section: Discussionmentioning

confidence: 95%

Genetic Enhancement of Calcitonin Gene-Related Peptide-Induced Central Sensitization to Mechanical Stimuli in Mice

Prado¹,

Hammond²,

Russo³

2009

The Journal of Pain

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Calcitonin gene-related peptide (CGRP) is a key player in migraine. To address the role of CGRP in mechanical allodynia, which is a common feature of migraine, we used CGRP-sensitized transgenic mice. These mice have elevated nervous system expression of the human receptor activity-modifying protein-1 (hRAMP1) subunit of the CGRP receptor. Under baseline conditions, the nestin/hRAMP1 mice and control littermates had similar hindpaw withdrawal thresholds to von Frey filaments. The effect of CGRP was tested using a filament that elicited a withdrawal response on 20% of its presentations. Following intrathecal injection of 1 nmol CGRP in the nestin/hRAMP1 mice, the response frequency was 80% within 30 min. The antagonist CGRP(8-37) blocked the increased response. In control littermates, a five-fold higher dose of CGRP was required to elicit a similar response. In contrast to intrathecal injection, peripheral CGRP did not increase the mechanical responses. Intraplantar injection of capsaicin was used to test the efficacy of endogenous CGRP. Capsaicin increased mechanical responses in the nestin/hRAMP1 and control mice, although a higher dose was required in controls. In contrast to control mice, there was also a contralateral paw response in nestin/hRAMP1 mice, which is consistent with central sensitization. PERSPECTIVE: In this study we show central CGRP-induced mechanical allodynia that is enhanced by overexpression of RAMP1 in nervous system. These data suggest that hypersensitivity to CGRP could be a potential mechanism underlying central sensitization in migraine and point to CGRP receptor antagonists as a possible therapy for other pain disorders.

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“…CGRP is released in the spinal dorsal horn by noxious stimulation and peripheral inflammation such as the K/C arthritis [ 26 , 34 , 35 ]. Peripheral inflammation also leads to changes in CGRP binding sites in the dorsal horn [ 32 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Pain-Related Synaptic Plasticity in Spinal Dorsal Horn Neurons: Role of CGRP

Bird

Han

et al. 2006

Mol Pain

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BackgroundThe synaptic and cellular mechanisms of pain-related central sensitization in the spinal cord are not fully understood yet. Calcitonin gene-related peptide (CGRP) has been identified as an important molecule in spinal nociceptive processing and ensuing behavioral responses, but its contribution to synaptic plasticity, cellular mechanisms and site of action in the spinal cord remain to be determined. Here we address the role of CGRP in synaptic plasticity in the spinal dorsal horn in a model of arthritic pain.ResultsWhole-cell current- and voltage-clamp recordings were made from substantia gelatinosa (SG) neurons in spinal cord slices from control rats and arthritic rats (> 6 h postinjection of kaolin/carrageenan into the knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of afferents in the dorsal root near the dorsal root entry zone. Neurons in slices from arthritic rats showed increased synaptic transmission and excitability compared to controls. A selective CGRP1 receptor antagonist (CGRP8-37) reversed synaptic plasticity in neurons from arthritic rats but had no significant effect on normal transmission. CGRP facilitated synaptic transmission in the arthritis pain model more strongly than under normal conditions where both facilitatory and inhibitory effects were observed. CGRP also increased neuronal excitability. Miniature EPSC analysis suggested a post- rather than pre-synaptic mechanism of CGRP action.ConclusionThis study is the first to show synaptic plasticity in the spinal dorsal horn in a model of arthritic pain that involves a postsynaptic action of CGRP on SG neurons.

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Changes in [125I]hCGRP binding in rat spinal cord in an experimental model of acute, peripheral inflammation

Cited by 24 publications

References 49 publications

Altered Calcitonin Gene‐related Peptide, Substance P and Enkephalin Immunoreactivities and Receptor Binding Sites in the Dorsal Spinal Cord of the Polyarthritic Rat

Altered Calcitonin Gene‐related Peptide, Substance P and Enkephalin Immunoreactivities and Receptor Binding Sites in the Dorsal Spinal Cord of the Polyarthritic Rat

Genetic Enhancement of Calcitonin Gene-Related Peptide-Induced Central Sensitization to Mechanical Stimuli in Mice

Pain-Related Synaptic Plasticity in Spinal Dorsal Horn Neurons: Role of CGRP

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