Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain

Abstract

Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-α) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-α up-regulation activates nuclear factor κB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-α and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-α inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy.

Administrations of thalidomide into the rostral ventromedial medulla alleviates painful diabetic neuropathy in Zucker diabetic fatty rats

“…While previous studies have shown 18 that systemic administrations of thalidomide can strongly prevent the mechanical allodynia and thermal hyperalgesia in streptozotocin (STZ)-induced type 1 diabetic neuropathy (Chauhan et al, 2012;Huang et al, 2014;Taliyan and Sharma 2012), our study first demonstrated that supraspinal mechanisms of thalidomide play a critical role in modulations of type 2 diabetes induced neuropathic pain. Our results further suggested that TNFα and IL-1β mediated NFκB signaling in the RVM may contribute to the modulations of type 2 diabetes induced neuropathic pain.…”

“…Furthermore, recent studies have shown that thalidomide can strongly prevent the mechanical allodynia and 5 thermal hyperalgesia in streptozotocin (STZ)-induced type 1 diabetic neuropathy (Chauhan et al, 2012;Huang et al, 2014;Taliyan and Sharma 2012). It has been reported that thalidomide can reduce the synthesis of TNFα and other pro-inflammatory cytokines including IL-1β (Sampaio et al, 1991;Singhal and Mehta 2002).…”

Administrations of thalidomide into the rostral ventromedial medulla produce antinociceptive effects in a rat model of postoperative pain

“…Importantly, recent research has shown that thalidomide treatment can reduce thermal hyperalgesia and allodynia in an animal model of neuropathic pain (Cata, Weng, & Dougherty, ), and strongly attenuate the mechanical allodynia in an animal model of type 1 diabetic neuropathy (Chauhan, Taliyan, & Sharma, ; Huang et al, ; Taliyan & Sharma, ). These effects likely involve the RVM, since intra‐RVM thalidomide treatment was able to dose‐dependently decrease mechanical allodynia in diabetic rats (Yang et al, ).…”

Involvement of peripheral TRPV1 channels in the analgesic effects of thalidomide

“…It then returned to the market mainly as a treatment for myelodysplastic syndrome and multiple myeloma due to its anticachectic, antiemetic, mildly hypnotic, anxiolytic, antiinflammatory and antiangiogenic properties. Moreover, there are reports and studies of thalidomide for the treatment of inflammatory and nociceptive pains as an analgesic or analgesic adjuvant in clinic due to its immunomodulatory and anti-inflammatory properties (Asher and Furnish, 2013;Belda et al, 1966;Chauhan et al, 2012;Ching et al, 2003;Peuckmann et al, 2003;Ribeiro et al, 2000;Schwartzman et al, 2003). Thalidomide can selectively suppress the production of tumor necrosis factor α (TNF-α) (Andrade et al, 2012;Klausner et al, 1996;Marriott, 1997;McHugh and Rowland, 1997;Piura et al, 2013;Schmidt et al, 1996), which plays a pivotal role in the generation of pains.…”