Topography of Primary Muscle Afferent Neurons in Rat Dorsal Root Ganglia: A Three-Dimensional Computer-Aided Analysis

Abstract INTRODUCTION Women are at greater risk to suffer from many chronic pain conditions, more often report painful symptoms in epidemiological studies, and demonstrate greater pain sensitivity to experimentally measured pain responses. There is growing evidence from animal models for sex-specific biological differences in nociception, particularly involving primary afferent neurons, that may contribute to these differences. However, the details and extent of sex-specific differences associated with pain in human afferent neurons has not been previously investigated. METHODS Human dorsal root ganglia (DRG) and medical histories were obtained from patients undergoing spinal surgery that necessitated sacrifice of spinal nerve roots as part of standard of care. Clinical data for presence of painful radiculopathy was obtained through retrospective review of medical records or collected at study enrollment. RNA sequencing (RNA-seq) was performed on 21 DRG from 15 patients with variable presence of radicular pain reported in a corresponding dermatome. Differential expression analysis for male w/pain (MP) vs female w/pain (FP) samples was performed with thresholds for robustly expressed autosomal genes (TPM >3.0), fold change of 2.0 or higher, with false discovery rate (FDR) <0.05. RESULTS Comparison of the MP and FP cohorts yielded 575 differentially expressed genes with 426 upregulated in MP and 149 upregulated in FP. Gene set enrichment analysis demonstrated significant differences in genes related to inflammation and immune regulation (increased MAPK and BDNF signaling in MP, increased Rhodopsin-like GPCR in FP) and differing clusters of spinal cord injury-associated genes (TLR4, AIF1, OMG, C1QB increased in FP, EGR1, NR4A1, ZFP36, BTG2, MYC in MP). CONCLUSION Utilizing RNA-seq of human DRG innervating regions of pain, this study provides the first demonstration of sex-specific differences for the biology of pain within the dorsal root ganglion in humans and implicates the immune system as a critical influence in these differences.

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Nociceptive Craniofacial Muscle Primary Afferent Neurons Synapse in Both the Rostral and Caudal Brain Stem

Journal of Neurophysiology ◽

10.1152/jn.00990.2006 ◽

2007 ◽

Vol 98 (1) ◽

pp. 214-223 ◽

Cited By ~ 20

Author(s):

Dean Dessem ◽

Masayuki Moritani ◽

Ranjinidevi Ambalavanar

Keyword(s):

Brain Stem ◽

Three Dimensional ◽

Field Testing ◽

Intracellular Recordings ◽

Afferent Neurons ◽

Limited Information ◽

Muscle Stretching ◽

Axon Collaterals ◽

Somatosensory Information ◽

Muscle Afferent

Limited information is available on muscle afferent neurons with fine fibers despite their presumed participation in musculoskeletal disorders, including temporomandibular disorders. To study these neurons, intracellular recordings were made from the central axons of slowly conducting muscle afferent neurons in anesthetized rats. After intraaxonal impalement, axons were characterized by masseter nerve stimulation, receptive field testing, muscle stretching and intramuscular injection of hypertonic saline. Intracellular recordings were made from 310 axons (conduction velocity: 6.5–60M/s, mean = 27.3M/s; following frequency: 27–250 Hz, mean = 110Hz). No neurons responded to cutaneous palpation or muscle stretching. Some axons ( n = 34) were intracellularly stained with biotinamide. These neurons were classified as group II/III noxious mechanoreceptors because their mechanical threshold exceeded 15 mN, and conduction velocities ranged from 12 to 40.2M/s (mean = 25.3M/s). Two morphological types were recognized by using an object-based, three-dimensional colocalization methodology to locate synapses. One type (IIIHTMVp-Vc) possessed axon collaterals that emerged along the entire main axon and synapsed in the trigeminal principal sensory nucleus and spinal trigeminal subnuclei oralis (Vo), interpolaris (Vi), and caudalis (Vc). A second type (IIIHTMVo-Vc) possessed axon collaterals that synapsed only in caudal Vo, Vi, and Vc. Our previous studies show that muscle spindle afferent neurons are activated by innocuous stimuli and synapse in the rostral and caudal brain stem; here we demonstrate that nociceptive muscle mechanoreceptor afferent axons also synapse in rostral and caudal brain stem regions. Traditional dogma asserts that the most rostral trigeminal sensory complex exclusively processes innocuous somatosensory information, whereas caudal portions receive nociceptive sensory input; the data reported here do not support this paradigm.

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