Bone cancer-induced pain is associated with glutamate signalling in peripheral sensory neurons

Abstract

We previously identified that several cancer cell lines known to induce nociception in mouse models release glutamate in vitro. Although the mechanisms of glutamatergic signalling have been characterized primarily in the central nervous system, its importance in the peripheral nervous system has been recognized in various pathologies, including cancer pain. We therefore investigated the effect of glutamate on intracellular electrophysiological characteristics of peripheral sensory neurons in an immunocompetent rat model of cancer-induced pain based on surgical implantation of mammary rat metastasis tumour-1 cells into the distal epiphysis of the right femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Activity of sensory neurons was measured by intracellular electrophysiological recordings in vivo. Glutamate receptor expression at the mRNA level in relevant dorsal root ganglia was determined by reverse transcription polymerase chain reaction using rat-specific primers. Nociceptive and non-nociceptive mechanoreceptor neurons exhibiting changes in neural firing patterns associated with increased nociception due to the presence of a bone tumour rapidly responded to sulphasalazine injection, an agent that pharmacologically blocks non-vesicular glutamate release by inhibiting the activity of the system x C À antiporter. In addition, both types of mechanoreceptor neurons demonstrated excitation in response to intramuscular glutamate injection near the femoral head, which corresponds to the location of cancer cell injection to induce the bone cancer-induced pain model. Therefore, glutamatergic signalling contributes to cancer pain and may be a factor in peripheral sensitization and induced tactile hypersensitivity associated with bone cancer-induced pain.

Ligand-Gated Ion Channels as Targets for Treatment and Management of Cancers

“…Glutamatergic signaling has also been shown to play a critical role in the peripheral sensitization and mechanical hypersensitivity associated with CIBP. Zhu et al (2020) showed that glutamate injection-induced neuronal excitation in dorsal root ganglia (DRG) is similar to that shown to be induced by CIBP. In a breast cancer model of CIBP, sulfasalazine reduced nociceptive perception and delayed onset of behavioral pain signs ( Ungard et al, 2014 ; Ellingson and Vanderah, 2020 ; Zhu et al, 2020 ).…”

“… Zhu et al (2020) showed that glutamate injection-induced neuronal excitation in dorsal root ganglia (DRG) is similar to that shown to be induced by CIBP. In a breast cancer model of CIBP, sulfasalazine reduced nociceptive perception and delayed onset of behavioral pain signs ( Ungard et al, 2014 ; Ellingson and Vanderah, 2020 ; Zhu et al, 2020 ). Furthermore, in a rat model of CIBP, direct inhibition of NMDAR in the spinal cord led to nociceptive relief ( Dai et al, 2017 ).…”

Multifarious Targets and Recent Developments in the Therapeutics for the Management of Bone Cancer Pain

“…Also, recently another study demonstrated the effect of an aberrant system x c by injecting glutamate intramuscularly in the BCP model. They treated the tumor implanted mice with sulfasalazine which modulates system x c and rectified the glutamate signaling leading to relief from pain behavior . This suggests that neurotrophins, their receptors, glutamate, and system x c played an important role in the peripheral sensitization during BCP and may serve as potential targets in the mitigation of the same.…”

Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination

“…To quantify this excitability, the threshold of depolarizing current pulses of 100 ms each, injected with an amplitude of 500 to 4000 pA in 500 pA increments into the soma was determined using the Protocol Editor function in pClamp 9.2. The conduction velocity (CV) was used to categorize DRG sensory neurons as follows: C-fiber neurons �0.8 mm/ms, Aδ-fiber neurons 1.5-6.5 mm/ms, and Aβ-fiber neurons >6.5 mm/ms [41,49]. The threshold of activation, the depth of the receptive field, and the pattern of adaption were the major factors used to further classify neurons into LTM, HTM, and unresponsive neurons [41,[49][50][51].…”

“…The conduction velocity (CV) was used to categorize DRG sensory neurons as follows: C-fiber neurons �0.8 mm/ms, Aδ-fiber neurons 1.5-6.5 mm/ms, and Aβ-fiber neurons >6.5 mm/ms [41,49]. The threshold of activation, the depth of the receptive field, and the pattern of adaption were the major factors used to further classify neurons into LTM, HTM, and unresponsive neurons [41,[49][50][51]. HTM neurons responded to noxious stimuli, including a noxious pinch and application of pointed objects such as the sharp end of a syringe needle, whereas LTM neurons responded to innocuous stimuli such as a moving brush, light pressure with a blunt object, a light manual tap, or vibration.…”