Calcitonin gene-related peptide 8-37 inhibits the evoked discharge frequency of wide dynamic range neurons in dorsal horn of the spinal cord in rats
Introduction
It has been reported that peripheral noxious stimulation results in the release of calcitonin gene-related peptide (CGRP) from primary afferent fibers in the dorsal horn of the spinal cord suggesting that it plays a role in the transmission of presumed nociceptive information [1], [2]. Recent works in our laboratory have demonstrated that intrathecal administration of CGRP8-37, a selective antagonist of CGRP receptors [3], [4], induced a significant increase in hindpaw withdrawal latency to noxious thermal and mechanical stimulation in rats [5], [6], [7], [8]. In contrast, Xu and Wiesenfeld-Hallin recently reported that intrathecal administration of CGRP8-37 facilitated a nociceptive reflex at the spinal cord level [9]. Furthermore, intrathecal injection of 26 pmol of CGRP induced a moderate facilitation of the reflex which was not antagonized by CGRP8-37 at doses ranging from 5.2 to 26 nmol. They concluded that CGRP8-37 cannot be useful as a spinal analgesic [9]. The present study was carried out to elucidate the effect of intrathecal administration of CGRP8-37 on the transmission of presumed nociceptive information in the spinal cord by recording the discharge frequency of wide dynamic range (WDR) neurons in the dorsal horn of the spinal cord in rats.
Section snippets
Animals and surgery
All experiments were performed on male Sprague–Dawley rats weighing 250 to 350 g. The rats were housed in cages with free access to food and water, and maintained in a room temperature of 24+2°C with a 12-h light/dark cycle. All experiments were conducted according to the guidelines of the animal ethical committee of Karolinska Institutet and every effort was made to minimize animal suffering.
The rats were anesthetized with pentobarbital sodium (35 mg/kg, intraperitoneally) and placed in a
Results
Three nmol of CGRP8-37 or 10 μl of 0.9% saline was applied directly on the dorsal surface of the spinal cord. Recordings were performed at the points of 1, 5, 10, 15, 20, 25 and 30 min after the administration of CGRP8-37 or saline. Fig. 1 shows the discharge frequency of a WDR neuron after administration of 0.9% saline (Fig. 1B) and the discharge frequency of the same one WDR neuron after administration of CGRP8-37 (Fig. 1A). As shown in Fig. 1A, a marked inhibitory effect on the discharge
Discussion
CGRP exists in the primary afferents within the dorsal horn of the spinal cord [13] and it is generally agreed that CGRP has an excitatory action [14], [15], [16]. The released peptides bind to the post-synaptic receptors thereby transmitting the afferent information further within the nociceptive system. Pohl et al. suggested that among the various types of natural noxious stimulation, noxious heat may selectively excite CGRP-containing A-δ and C primary afferent fibers projecting within the
Conclusion
Intrathecal administration of 3 nmol of CGRP8-37 significantly decreased the evoked discharge frequency of WDR neurons, an effect lasting for 30 min. The results indicate that CGRP receptors play an important role in the transmission of presumed nociceptive information in the dorsal horn of the spinal cord.
Acknowledgements
This study was supported by funds from Karolinska Institutet, Wenner-Gren Center Foundation, Natural Science Pre-Research Foundation of Peking University and National Natural Science Foundation of China (NSFC).
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Roles of calcitonin gene-related peptide and its receptors in pain-related behavioral responses in the central nervous system
2009, Neuroscience and Biobehavioral ReviewsNociceptive transmitter release in the dorsal spinal cord by capsaicin-sensitive fibers after noxious gastric stimulation
2005, Brain ResearchCitation Excerpt :Immunohistochemistry also revealed that CGRP is more extensively distributed than SP in cell bodies of gastric afferents in thoracic DRGs, suggesting that this peptide plays a special role in the stomach–spinal cord pathway [10]. Previous studies have shown that CGRP is released in the dorsal horn of the spinal cord following somatic noxious stimulation and inflammation [6,23] and that its receptor is involved in excitation of nociceptive wide dynamic neurons of the dorsal horn and the generation of hyperalgesia [32,39]. In accordance, CGRP knock out mice fail to show secondary hyperalgesia in knee joint inflammation [40].