Effect of Acute Administration of Caffeine on Neuropathic Pain and the Role of Nitric Oxide Pathway in an Animal Model of Chronic Constriction Injury

Abstract

Introduction: Partial peripheral nerve injury often results in chronic pain, including hyperalgesia and allodynia. Caffeine, as a non-selective antagonist of adenosine receptors (ARs), has protective effects on neuropathic pain. Since nitric oxide (NO) is partially involved in the central effects of caffeine, we investigated the effects of acute caffeine administration on neuropathic pain, focusing on A₁ and A₂ receptors and the possible role of NO.

Methods: Following chronic constriction injury (CCI), male Wistar rats were administered caffeine (10, 50, and 100 mg/kg). Also, groups of animals received L-NAME (30 mg/kg) or L-arginine (100 mg/kg) either alone or before treatment with 50 mg/kg of caffeine. Rats were tested for hyperalgesia and allodynia at 4, 7, 14, 21, and 28 days following CCI.

Results: Administration of 10 mg/kg of caffeine significantly increased cold allodynia, while 50 and 100 mg/kg of caffeine decreased mechanical allodynia and thermal hyperalgesia. Pre-treatment with L-NAME before caffeine administration decreased cold and mechanical allodynia and thermal hyperalgesia. Treatment with L-arginine before caffeine administration increased thermal hyperalgesia and decreased cold allodynia.

Conclusion: The present data show that caffeine dose-dependently affects the pro-analgesic or anti-analgesic states in the CCI model.

Keywords: Adenosine receptors (ARs); Caffeine; L-Arginine; L-NAME; Neuropathic pain; Nitric oxide (NO).

Figure 1.

Heat hyperalgesia after CCI injury A) Hyperalgesia in CCI rats and sham animals (^**P<0.01, ^***P<0.001 CCI vs sham group) B) Effect of different doses of Caf (10, 50, and 100) on hyperalgesia (^***P<0.001 Caf.50 vs CCI+saline group, ^&P<0.05, ^&&P<0.01, ^&&&P<0.001 Caf.100 vs CCI+saline group) C) Effect of L-NAME or L-NAME+Caf on hyperalgesia (^***P<0.001, Caf.50 vs CCI+saline group, ^&P<0.05, ^&&P<0.01, ^&&& P<0.001, L-NAME vs CCI+saline group, ^{^^}P<0.01, ^{^^^}P<0.001, L-NAME+Caf vs CCI+saline group, ⁺⁺P<0.01, ⁺⁺⁺P<0.001, L-NAME+Caf vs Caf.50 group. #P<0.05 L-NAME+Caf vs L-NAME group) D) Effect of L-ARG or L-ARG+Caf on hyperalgesia (^***P<0.001, Caf.50 vs CCI+saline group, ⁺⁺P<0.01, L-ARG+Caf vs Caf.50 group)

Figure 2.

Mechanical allodynia after CCI injury A) Mechanical allodynia in CCI rats and sham animals (^**P<0.01 CCI vs sham group) B) Effect of different doses of Caf (10, 50, and 100) on mechanical allodynia (^*P<0.05, ^***P<0.001 Caf.50 vs CCI+saline group, ^&P<0.05, ^&&&P<0.001 Caf.100 vs CCI+saline group) C) Effect of L-NAME or L-NAME+Caf on mechanical allodynia (^*P<0.05, ^***P<0.001 Caf.50 vs CCI+saline group, ^&P<0.05, ^&&&P<0.001 L-NAME vs CCI+saline group, ^{^}P<0.05, ^{^^^}P<0.001 L-NAME+Caf vs CCI+saline group) D) Effect of L-ARG or L-ARG+Caf on mechanical allodynia (^*P<0.05, ^***P<0.001 Caf.50 vs CCI+saline group)

Figure 3.

Cold allodynia after CCI injury A) Cold allodynia in CCI and sham animals (^***P<0.001 CCI vs sham group) B) Effect of Caf (10, 50, and 100) on cold allodynia (^*P<0.05, ^**P<0.01, ^***P<0.001 Caf.10 vs CCI+saline group) C) Effect of L-ARG or L-ARG+Caf on cold allodynia (^*P<0.05, ^**P<0.01, L-ARG+Caf vs CCI+saline group, ^##P<0.01, ^###P<0.001, L-ARG+Caf vs Caf.50 group, ^&P<0.05 L-ARG+Caf vs L-ARG group) D) Effect of L-NAME or L-NAME+Caf on cold allodynia (^*P<0.05, ^**P<0.01, L-NAME vs CCI+saline group, ^&P<0.05, ^&&P<0.01 L-NAME+Caf vs CCI+saline group, ⁺⁺P<0.01, ⁺⁺⁺P<0.001, L-NAME+Caf vs Caf.50 group)