Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague–Dawley rats (200–250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca2+]i in dorsal root ganglia (DRG) neurons ex vivo. Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.

The Use of CBD and Its Synthetic Analog HU308 in HIV-1-Infected Myeloid Cells

“…CB2 is expressed mainly in the immune system [ 57 ], while the CBD receptors are within CNS and throughout the body (i.e., TRPV1 is found on neurons in epithelial cells [ 58 , 59 ]). These receptors are part of the G-coupled protein receptors and are pharmacologic targets of interest as they control inflammation as well as other sensations (i.e., pain) [ 37 , 60 , 61 , 62 , 63 ]. Thus, it is not surprising that HU308 has been shown to decrease peripheral and ocular inflammation [ 55 , 61 ].…”

“…It has been shown that to reduce the pain associated with chronic inflammation, both CB2 and TRPV1 are beneficial. Thus, targeting both receptors should be considered in future studies [ 60 , 80 ]. Furthermore, longevity studies should be done to determine effects of long-term drug use with CBD or HU308 in combination with cART, especially in regards to latency.…”

I Feel! Therefore, I Am from Pain to Consciousness in DOC Patients

“…Interestingly, there is an overlap between the opioid and cannabinoid systems in pain modulation. Both systems, connected through GPCRs, share similar intracellular signaling pathways, suggesting a synergistic effect between cannabinoids and opioids for pain relief [49].…”

Adenosine Receptors as Potential Therapeutic Analgesic Targets

“…New drugs and therapies are required because a safe and effective treatment for chronic pain has not yet been developed. Pharmaceutical research focuses on effective analgesic drugs, with G-protein-coupled receptors (GPCRs) being a key focus in pain-relieving medication development [8][9][10]. Among them, adenosine metabotropic receptors (AR) modulators are increasingly being implicated in the antinociceptive and/or antihyperalgesic effects seen in various chronic pain models [2,[11][12][13].…”