Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion

Abstract

Peripheral neuropathy presents as a combination of positive (e.g., pain) and negative symptoms (e.g., sensory loss), which vary across disease conditions [23; 76]. As pathophysiological mechanisms of pain cannot be examined in patients, an examination of pain phenotypes helps provide clues to the underlying mechanisms [41; 76]. A subset of oral cancer patients exhibits symptoms suggestive of peripheral neuropathy such as intractable pain, function impairment, numbness, and formication [5; 44]. As diagnosis of nerve injury requires anatomical examination [34] that is challenging in patients, we seek to gain mechanistic insight by examining pain phenotypes in patients.Neuropathic pain caused by peripheral disorders is predominantly driven by primary afferent neurons including both myelinated A-and unmyelinated C-fibers [20; 23]. Altered electrophysiological properties, along with neurochemical and anatomical changes in sensory neurons, contribute to different pain phenotypes following nerve injury [20; 23; 41]. The impact of PNI on electrophysiological and neuroanatomical properties of primary afferent neurons remains unknown.We hypothesize that peripheral nerve injury and hypersensitive primary afferent neurons contribute to PNI-induced pain in oral cancer. We compared pain in oral cancer patients with and without PNI evaluated with a validated oral cancer pain questionnaire [47] that quantifies two prominent features of neuropathic pain -spontaneous pain (i.e., pain felt without obvious external stimuli) and mechanical allodynia (i.e., pain resulting from a nonpainful stimulus) [41; 50; 58]. We produced a model of PNI-induced pain and probed the peripheral mechanisms using in vivo intracellular recordings and electron microscopic analysis of nerve ultrastructure. Methods PatientsA pre-existing database composed of a cohort of 69 oral cancer patients referred to Bluestone Center for Clinical Research and Oral Cancer Center at New York University College of Dentistry from 2010-2017 was used for data analysis. All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee (NYU IRB #10-01261) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients provided written informed consent prior to inclusion in the study. The database contains information for each patient including age, sex, racial/ethnic identity (white, Hispanic, Africa-American, Asian), drinking/smoking history (previous, never, current), and pathological information including the presence (yes or no) of PNI, lymphovascular invasion, extracapsular spread, nodal status, tumor staging (T1-4), and tumor thickness/depth of invasion. Nodal status was classified as node positive (N+) or negative (N0) by pathological examination of the neck dissection specimen following surgery. Anatomical location of the oral cancer (Supplemental Figure 1) includes tongue (55.1%), mandibular gingiva (23.2%), maxillary gingiva (7.25%),...

TNFα promotes oral cancer growth, pain, and Schwann cell activation

“…7 d). To examine the effect of Schwann cell activation on cancer pain in vivo, we used a sciatic nerve perineural invasion (PNI) model that is known to induce Schwann cell activation 13 , 40 , 41 . We used sham mice that received only the incision but no cancer implantation as a control.…”

“…Cancer- or hypoxia-activated Schwann cells release nociceptive mediators such as IL-6, TNFα, CXCL2, and IL-8 11 , 15 ; these mediators could sensitize primary afferent neurons to cause pain. Schwann cell activation causes myelin breakdown 41 ; the loss of structural support and insulation by myelin sheath breakdown is another possible explanation of pain produced by activated Schwann cells.…”

“…Athymic NU/J mice were anesthetized using isoflurane and their right sciatic nerve was exposed 41 . Oral cancer cells (1.5 × 10 4 HSC-3 cells in 3 μl DMEM, n = 10) or PBS (sham, n = 5) were injected into the sciatic nerve, distal to the bifurcation of the tibial and common peroneal nerves.…”

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

“…Condition place aversion (Havelin et al, 2017) Oral cancer Mechanical Von frey (Pickering et al, 2008;Ye et al, 2018;Salvo et al, 2020) Thermal…”

“…Hargreaves (Ye et al, 2012;Ye et al, 2014;Salvo et al, 2020) Functioninduced Dolognawmeter (Ye et al, 2011;Lam et al, 2012;Scheff et al, 2017;Scheff et al, 2018;Ye et al, 2018;Scheff et al, 2020) Spontaneous CPP (Chodroff et al, 2016;Scheff et al, 2019) Pancreatic cancer…”