Amitriptyline influences the mechanical withdrawal threshold in bone cancer pain rats by regulating glutamate transporter GLAST

Abstract

Patients with cancer, especially breast, prostate, and lung cancer, commonly experience bone metastases that are difficult to manage and are associated with bone cancer pain. Amitriptyline is often used to treat chronic pain, such as neuropathic pain. In this study, the effects of amitriptyline on the mechanical withdrawal threshold and its underlying mechanisms were evaluated in rat models of bone cancer pain. Walker 256 rat mammary gland carcinoma cells were injected into the bone marrow cavity of the right tibia of rats to provoke bone cancer pain. Then, amitriptyline was intraperitoneally administered twice daily from fifth day after the operation. Rats with bone cancer showed an apparent decline in the mechanical withdrawal threshold at day 11 after Walker 256 cells inoculation. The levels of the glutamate-aspartate transporter in the spinal cord dorsal horn decreased remarkably, and the concentration of the excitatory amino acid glutamate in the cerebrospinal fluid increased substantially. Amitriptyline injection could prevent the decline of mechanical withdrawal threshold in bone cancer pain rats. In addition, glutamate-aspartate transporter was upregulated on the glial cell surface, and glutamate levels were reduced in the cerebrospinal fluid. However, amitriptyline injection could not prevent the bone cancer pain-induced reduction in glutamate-aspartate transporter in the glial cell cytosol, it further downregulated cytosolic glutamate-aspartate transporter. Amitriptyline had no significant effect on GLAST messenger RNA expression, and bone cancer pain-invoked protein kinase A/protein kinase C upregulation was prevented. Taken together, these results suggest that the intraperitoneal injection of amitriptyline can prevent the decrease of mechanical withdrawal threshold in bone cancer pain rats, the underlying mechanisms may be associated with the inhibition of protein kinase A/protein kinase C expression, thus promoting glutamate-aspartate transporter trafficking onto the glial cell surface and reducing excitatory amino acid concentrations in the cerebrospinal fluid.

Loss of astrocytic A1 adenosine receptor is involved in a chemotherapeutic agent–induced rodent model of neuropathic pain

“…In a mouse model of bone cancer pain, the expression level of spinal glutamate transporter protein gradually decreased with the development of the disease course. 40 In rats with chronic constriction injury and spinal nerve ligation-induced neuropathic pain models, the uptake activity of glutamate in the spinal cord was decreased. 40,41 The results of this experiment show that, after OXA administration, the expressions of GS and GLT-1 proteins in the spinal cord decreased significantly, which may be the direct reason for the decrease in pain threshold and central sensitization in mice.…”

“…40 In rats with chronic constriction injury and spinal nerve ligation-induced neuropathic pain models, the uptake activity of glutamate in the spinal cord was decreased. 40,41 The results of this experiment show that, after OXA administration, the expressions of GS and GLT-1 proteins in the spinal cord decreased significantly, which may be the direct reason for the decrease in pain threshold and central sensitization in mice. However, the mechanism of this decrease remains unclear.…”

“…Our experimental observations are consistent with this underlying biology. In a mouse model of bone cancer pain, the expression level of spinal glutamate transporter protein gradually decreased with the development of the disease course 40 . In rats with chronic constriction injury and spinal nerve ligation–induced neuropathic pain models, the uptake activity of glutamate in the spinal cord was decreased 40,41 .…”