The overall goals are focused on studying and characterizing the mammalian somatosensory system's physiological functions in normal and pathological conditions (including nerve injury and cancer pain).
Specifically, the focus is on the molecular basis of the mechanical transduction on primary sensory neurons and the circuits, architecture, and sensory integration in secondary-order sensory neurons in the spinal cord. For this task, we use a combination of different techniques, including unique proficiency in whole animal in vivo intracellular electrophysiology and pharmacology, immunohistochemical (ICC), neuroanatomical characterization (confocal microscopy and 3D reconstructions), reflexive and non-reflexive behavior and several molecular techniques (e.g. Single-cell PCR)
The unparalleled resolution afforded by this challenging and detailed single-neuron approach has provided several novel insights into sensory neuron biology, particularly concerning the anatomical and functional diversity of nociceptors and their interaction with tactile afferents at multiple levels on the superficial dorsal horn
Funding: NIH/REJOIN UC2GRANT13593949
My lab has pioneered single-cell research on the mammalian trigeminal system (TG) in living mammals. As a Ph.D. student, I developed surgical techniques to make it possible to access the TG of living mice and perform intracellular recording. My observations demonstrated that the TG has unique cellular composition and biophysical properties compared to the rest of the somatosensory system (Fig. 1). The TG system is biased toward nociceptive afferents with high-speed conductivity (fast nociceptors [A-HTMR]) and is highly susceptible to the development of hyperexcitability after injury or disease (Cancer) (1,2).
Based on these significant findings and my unique technical proficiency, I currently collaborate (as a leading Co-PI) in the most important effort to date on TG neurobiology. By invitation of the University of Texas, I have joined an international team (University of Texas, Wake Forest University, and Karolinska Institute [Sweden]) to address the NIH REJOIN initiative and uncover the cellular entities (and their genetic makeup) innervating the TG and its plasticity after injury (temporomandibular disorders [TMD]).
|Figure 1. Example of a TG afferent (AHTMR) innervating the masseter muscle, stained with 5% NB for single-cell PCR. A. Diagram of the relative locations of the cellular RF (left) and its cellular body at the TG (right). B. CV (latency: 2.4 ms, distance to the ganglia: 12.1 mm = 5 m/s) and AP shape (left) and cellular response to the SAP protocol of intracellular current (IC) application (200 ms pulses). C. Detail of the cellular RF sensibility to punctate mechanical stimulation and MT (left) and tonic activation (3xMT) and SA (right). D. Result of the cellular body staining with 5% NB and the cellular reactivity to CGRP and TRPM8 antibodies (example for preliminary results only). Scale bars: 20 mV, 2 ms (B. right: 10 sec (C, left), 5 sec (C, right), 20 um (D).|
Funding: NIH 1P01NS119159-01A1
During the last decade, my lab has intensified efforts to understand and characterize the effects of injury on the PNS. These efforts have led to groundbreaking discoveries such as the extensive distribution of peripheral and central terminals of A-HTMRs (3) (Fig. 2), the opposing effects of injury on tactile and mechano-nociceptive afferents (4), leading to the development of the first textured surface (NOX system) to generate nociceptive stimulation selectively after injury in the behaving animal (5), the existence of endogenous electrical damping mechanisms to control A-HTMR hyperexcitability (post-discharge hyperpolarization [PDH]) (6) and the discovery of the "butterfly effect," the injury-induced collapse of mechanical sensibility to a common level by desensitization in tactile and sensitization in mechano-nociceptive afferents returning to divergence over weeks of behavioral recovery (7) (Fig. 3).
Based on these observations and seminal data on the effects of OXT on the electrical signature of PNS sensory neurons (8), I was able to propose and successfully fund an NIH P01 multicenter program (Wake Forest University, Standford University, and Linkoping University [Sweden]). This program will study the published neuropharmacological effects of OXT on the return of injury-induced opposing effects on tactile and mechano-nociceptors after injury in intracellular studies in animals and psychophysical and microneurography studies in humans.
|Figure 2. 3D distribution diagram of the single-cell staining (20% NB) of a AHTMR nociceptive afferent (blue) central arborization vs C-nociceptive afferents (red) across superficial laminae (LI and LII, green). Adapted from Boada and Woodbury (2008).||
Figure 3. Somatosensory neurons (tactile, black, nociceptive, white) response to nerve injury (L5 pSNL) . Adapted from Boada MD et al. (2020).
My latest efforts to understand the complicated interaction between cancer cells and sensory neurons (PSN) including neurogenic control of tumor growth. So far, my observations in collaboration with NYU (Dr. Yi Ye) suggest that specific cancer cell lines recruit the PSN to enhance local tumor growth and metastasis.
My efforts in this area include the development of the appropriate models to study this interaction (9), the study of the effects of naturally implanted tumor growth in the TG system (corroborating the impact of injury on the activation patterns of PSN) (2), and currently the use of this information for the development of experimental treatments (the translational aspect of cancer/pain neurobiology). These striking data have several implications for the patient's treatment and further extent the role of the PSN plasticity from a mere detection role to an active participant in disease development and immune response.
- Boada MD. Relationship between electrophysiological signature and defined sensory modality of trigeminal ganglion neurons in vivo. J Neurophysiol. 2013 Feb;109(3):749-57. doi: 10.1152/jn.00693.2012. Epub 2012 Nov 14. PMID: 23155179.
- Gutierrez S, Eisenach JC, Boada MD. Seeding of breast cancer cell line (MDA-MB-231LUC+) to the mandible induces overexpression of substance P and CGRP throughout the trigeminal ganglion and widespread peripheral sensory neuropathy throughout all three of its divisions. Mol Pain. 2021 Jan-Dec;17:17448069211024082. doi: 10.1177/17448069211024082. PMID: 34229504; PMCID: PMC8267036.
- Boada MD, Woodbury CJ. Myelinated skin sensory neurons project extensively throughout adult mouse substantia gelatinosa. J Neurosci. 2008 Feb 27;28(9):2006-14. doi: 10.1523/JNEUROSCI.5609-07.2008. PMID: 18305235; PMCID: PMC6671842.
- Boada MD, Eisenach JC, Ririe DG. Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature. J Neurophysiol. 2016 Jan 1;115(1):546-53. doi: 10.1152/jn.00796.2015. Epub 2015 Nov 18. PMID: 26581873; PMCID: PMC4760509.
- Boada MD, Martin TJ, Ririe DG. Nerve injury induced activation of fast-conducting high threshold mechanoreceptors predicts non-reflexive pain related behavior. Neurosci Lett. 2016 Oct 6;632:44-9. doi: 10.1016/j.neulet.2016.08.029. Epub 2016 Aug 17. PMID: 27544012; PMCID: PMC5310223.
- Boada MD, Ririe DG, Eisenach JC. Post-discharge hyperpolarization is an endogenous modulatory factor limiting input from fast-conducting nociceptors (AHTMRs). Mol Pain. 2017 Jan-Dec;13:1744806917726255. doi: 10.1177/1744806917726255. PMID: 28825337; PMCID: PMC5570122.
- Boada MD, Martin TJ, Parker R, Houle TT, Eisenach JC, Ririe DG. Recovery from nerve injury induced behavioral hypersensitivity in rats parallels resolution of abnormal primary sensory afferent signaling. Pain. 2020 May;161(5):949-959. doi: 10.1097/j.pain.0000000000001781. PMID: 32040074; PMCID: PMC7166146.
- Boada MD, Gutierrez S, Eisenach JC. Peripheral oxytocin restores light touch and nociceptor sensory afferents towards normal after nerve injury. Pain. 2019 May;160(5):1146-1155. doi: 10.1097/j.pain.0000000000001495. PMID: 30920428; PMCID: PMC9523380.
- Salvo E, Campana WM, Scheff NN, Nguyen TH, Jeong SH, Wall I, Wu AK, Zhang S, Kim H, Bhattacharya A, Janal MN, Liu C, Albertson DG, Schmidt BL, Dolan JC, Schmidt RE, Boada MD, Ye Y. Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion. Pain. 2020 Nov;161(11):2592-2602. doi: 10.1097/j.pain.0000000000001986. PMID: 32658150; PMCID: PMC7572698.