Calcitonin gene-related peptide-immunoreactive nerve fibers in mandibular periosteum of rat: Evidence for primary afferent origin

doi:10.1016/0304-3940(88)90347-3

Neuroscience Letters

Volume 85, Issue 2, 29 February 1988, Pages 172-178

https://doi.org/10.1016/0304-3940(88)90347-3 Get rights and content

Abstract

Peptidergic neurons may play a role in the local regulation of bone mineralization. The neuropeptide vasoactive intestinal peptide (VIP) increases bone resorption in vitro, while calcitonin gene-related peptide (CGRP) has been shown to inhibit bone resorption in vitro. We have previously reported that sympathetic nerves with VIP-immunoreactivity innervate bone and periosteum. In the present study we sought to determine if CGRP fibers, like VIP fibers, exist in periosteum and what their origin might be. In whole-mount preparations of mandibular periosteum from rat, CGRP- and VIP-immunoreactive (IR) nerve fibers were present as networks within the periosteum. In preparations using two-color immunofluorescence, most CGRP-IR fibers were also immunoreactive for substance P (SP). In rats in which the subperiosteal space subjacent to the mandibular molars was injected with Fast blue or Fluoro-gold, retrogradely labeled cells were seen in ipsilateral trigeminal ganglia, superior cervical ganglia, and nodose ganglia. Individual cells labeled with both CGRP immunoreactivity and retrograde tracer were seen only in the mandibular portion of the trigeminal ganglion. These data suggest that CGRP-IR nerve fibers in periosteum may be of primary afferent origin. Given the reported effects of CGRP on bone mineralization, the present results suggest that primary afferent nerves containing CGRP and SP, as well as sympathetic nerves containing VIP, may play a role in focal bone remodeling.

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Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.
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This tissue is exclusively innervated by nociceptive afferents. In previous studies, CGRP-containing trigeminal ganglion neurons innervate blood vessels and make nerve plexuses in the periosteum (Hill & Elde, 1988, 1991). Because neonatal capsaicin treatment decreases the CGRP-containing nerve fibers (Hill & Elde, 1991), occurrence of TRPV1 has been also predicted in the periosteum.
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Double immunofluorescence method for TRPV1 and TRPV2 ion channels or ATP receptor P2 × 3 with calcitonin gene-related peptide (CGRP) was performed on trigeminal ganglion neurons retrogradely labeled from the mandibular periosteum, masseter muscle, or facial skin in 15 male Wistar rats.
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Consequently, the somatosensory cortical representation of inputs arising from bone has been neglected. Primary afferent fibers that innervate bone are small diameter myelinated or unmyelinated fibers (Furusawa, 1970; Ivanusic et al., 2006; Mach et al., 2002; Seike, 1976), contain substance P (SP) and calcitonin gene-related peptide (CGRP) (Bjurholm et al., 1988; Gronblad et al., 1984; Hill and Elde, 1988; 1991; Mach et al., 2002), and are responsive to noxious chemical and mechanical stimuli (Furusawa, 1970; Sakada and Taguchi, 1971; Seike, 1976). These findings are consistent with a role for these fibers in bone nociception.
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Calcitonin gene-related peptide-immunoreactive nerve fibers in mandibular periosteum of rat: Evidence for primary afferent origin

Abstract

J. Invest. Dermatol.

Neurosci. Lett.

Arch. Oral Biol.

Brain Res.

Neuroscience

Neuropeptides

Arch. Oral Biol.

The changing face of autonomic neurotransmission

Acta Physiol. Scand.

Human synthetic calcitonin gene-related peptide inhibits bone resorption in vitro

Endocrinology

Innervation of human bone periosteum by peptidergic nerves

Anat. Rec.

Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers

Science

Vasoactive intestinal peptide stimulates bone resorption via a cyclic adenosine 3′,5′-monophate dependent mechanism

Endocrinology