Spinal nociceptive transmission by mechanical stimulation of bone marrow

Abstract

BackgroundSince bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin.ResultsIntraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation.ConclusionsThe results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain in the corresponding skin fields. These mechanisms might contribute to pain caused by skeletal diseases.

Molecular Mechanisms That Contribute to Bone Marrow Pain

“…C nociceptors are small-diameter unmyelinated sensory neurons that encode slow, aching pain of the sort experienced in more chronic conditions, such as osteoarthritis or bone cancer. Both Aδ- and C-fiber sensory neurons innervate the bone marrow ( 31 – 36 ), contain molecular markers for nociceptors, such as substance P, calcitonin gene-related peptide (CGRP), tropomyosin receptor kinase A (TrkA), and transient receptor potential cation channel subfamily V member 1 (TRPV1) ( 33 , 35 , 37 – 42 ), and are responsive to noxious chemical and mechanical stimuli ( 31 , 32 , 42 – 45 ). Some larger diameter sensory neurons with specialized/encapsulated nerve terminal endings have been reported in the mandibular periosteum of cats ( 46 , 47 ), human long bone periosteum ( 48 ), and Haversian canals in canine cortical bone ( 49 ), but not in the bone marrow.…”

“…Fos is used routinely to study activity dependent changes in central neurons that are activated either directly, or indirectly by input from peripheral nociceptors, and the superficial dorsal horn of the spinal cord has a well-established role in processing of nociceptive input ( 52 ). Spinal dorsal horn neurons also respond to balloon inflation within the bone marrow of the rat femur ( 36 ), and electrical stimulation of nerves that enter the bone marrow of the cat humerus generates evokes potentials in topographically relevant areas of the primary and secondary somatosensory cortices ( 53 ). These findings are consistent with a primary role for sensory neurons that innervate the bone marrow in nociception.…”

Identifying spinal afferent (sensory) nerve endings that innervate the marrow cavity and periosteum using anterograde tracing

“…Pain is associated with most bony pathologies and it puts a significant burden (both in terms of quality of life and cost) on individuals, society, and the health care system all over the world. Small diameter myelinated and unmyelinated sensory neurons innervate both the periosteum and the marrow cavity (Furusawa, ; Ishida, Tanaka, Sekiguchi, Sugiyama, & Kawamata, ; Ivanusic, ; Ivanusic, Mahns, Sahai, & Rowe, ; Mach et al, ; Seike, ), and there is a rapidly growing body of evidence demonstrating that they are responsive to noxious chemical and/or mechanical stimuli (Ivanusic, Mahns, Sahai, Vickery, & Rowe, ; Morgan, Nencini, Thai, & Ivanusic, ; Nencini & Ivanusic, ; Nencini et al, ; Nencini et al, ; Nencini, Thai, & Ivanusic, ). Most previous work in the context of bone pain has focused on studying myelinated (Aδ‐fiber) nociceptors, and/or peptidergic unmyelinated (C‐fiber) nociceptors, because these have been the easiest to identify immunohistochemically (Castaneda‐Corral et al, ; Chartier et al, ; Imai et al, ; Mach et al, ).…”

Bone Metastasis Pain, from the Bench to the Bedside

“…Bone metastases can then induce CIBP in several ways, many of which are still under investigation [61,62]. Indeed, bone is a richly innervated tissue, and sensitive neurons can be found in both the periosteum [63,64] and the bone marrow [65,66]. Among these, the most abundant are nociceptors—which mediate acute and chronic bone pain—which will be the focus of the present review article.…”