Repeated injections of isovaline lead to analgesic tolerance and cross-tolerance to salicylate but not to morphine in male mice

Abstract

Tolerance to the antinociceptive effects of opioids is a major concern. Studies have shown that chronic use of non-steroidal anti-inflammatory (NSAIDs) causes significant tolerance and cross-tolerance to morphine. Chronic NSAIDs use can increase the risk of certain diseases, such as peptic ulcers, and exacerbate others, like heart failure. Therefore, developing novel pharmacological approaches could provide considerable benefits for chronic therapeutic procedures. Isovaline with a chemical structure similar to glycine and GABA induce a significant analgesic effect through GABA-B receptors. In this study, we investigated the impact of both short-term and long-term use of isovaline on the immediate response to pain, as well as the development of analgesic tolerance through daily injection (i.p.) of isovaline (100 mg/kg) for 5 days in male Balb/c mice. Additionally, on day 6, we examined the potential for cross-tolerance between isovaline and sodium salicylate (300 mg/kg) or morphine (5 mg/kg). The findings showed that isovaline injection resulted in a delayed onset of analgesic effect, a lowered peak effect, and less cumulative pain relief compared with sodium salicylate and morphine. This analgesic effect gradually decreased over the five days of isovaline injection. When sodium salicylate was injected into isovaline-tolerant mice, the antinociceptive effect decreased, suggesting cross-tolerance to sodium salicylate. However, no such tolerance was observed following morphine injection. Accordingly, it seems that chronic isovaline may interact with the sodium salicylate analgesic pathway but not with morphine.

Keywords

anti-nociception - morphine - salicylate - isovaline - cross-tolerance - hot plate

• References

• 1 Trujillo KA. The neurobiology of opiate tolerance, dependence and sensitization: mechanisms of NMDA receptor-dependent synaptic plasticity. Neurotoxicity research 2002; 4: 373-391
• 2 Déciga-Campos M, López UG, Reval MIDA. et al. Enhancement of antinociception by co-administration of an opioid drug (morphine) and a preferential cyclooxygenase-2 inhibitor (rofecoxib) in rats. European journal of pharmacology 2003; 460: 99-107
• 3 Pernia-Andrade AJ, Tortorici V, Vanegas H. Induction of opioid tolerance by lysine-acetylsalicylate in rats. Pain 2004; 111: 191-200
• 4 MacLeod BA, Wang JT, Chung CC. et al. Analgesic properties of the novel amino acid, isovaline. Anesthesia & Analgesia 2010; 110: 1206-1214
• 5 Kvenvolden KA, Lawless JG, Ponnamperuma C. Nonprotein amino acids in the Murchison meteorite. Proceedings of the National Academy of Sciences 1971; 68: 486-490
• 6 Enna S, McCarson KE. The role of GABA in the mediation and perception of pain. Advances in pharmacology 2006; 54: 1-27
• 7 Cooke J, Mathers D, Puil E. R-isovaline: a subtype-specific agonist at GABAB-receptors?. Neuroscience 2012; 201: 85-95
• 8 Shiba K, Mori H, Hisada K. Analogues of α-aminoisobutyric acid with various alkyl groups as potential tumour imaging agents; effects of chain length on tumour and normal tissue specificity. Nuclear Medicine Communications 1989; 10: 751-758
• 9 Trujillo KA. Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? A review of preclinical studies. Psychopharmacology 2000; 151: 121-141
• 10 Gurtskaia G, Tsiklauri N, Nozadze I. et al. An overview of antinociceptive tolerance to non-steroidal anti-inflammatory drugs. Annual Research & Review in. Biology 2014; 1887-1901
• 11 Yilmaz I, Ulugol A. The effect of nitric oxide synthase inhibitors on the development of analgesic tolerance to dipyrone in mice. International Journal of Neuroscience 2009; 119: 755-764
• 12 Gholami M, Moradpour F, Semnanian S. et al. Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons. European journal of pharmacology 2015; 767: 165-174
• 13 Sadegh M, Fathollahi Y, Javan M. et al. Tolerance to anti-nociceptive effects of sodium-salicylate and morphine decreases adenosine deaminase activity in the rat hippocampus. Koomesh. 2012 13. 390-397
• 14 Moskowitz AS, Terman GW, Carter KR. et al. Analgesic, locomotor and lethal effects of morphine in the mouse: strain comparisons. Brain research 1985; 361: 46-51
• 15 Naik V, Agshikar N, Abraham G. Analgesic and anti-inflammatory activity in alcoholic extracts of Cucumis trigonus Roxburghii: a preliminary communication. Pharmacology 1980; 20: 52-56
• 16 Whitehead RA, Schwarz SK, Asiri YI. et al. The efficacy and safety of the novel peripheral analgesic isovaline as an adjuvant to propofol for general anesthesia and conscious sedation: a proof-of-principle study in mice. Anesthesia & Analgesia 2015; 121: 1481-1487
• 17 Sadegh M, Fathollahi Y, Javan M. et al. Tolerance to anti-nociceptive effects of sodium-salicylate and morphine decreases adenosine deaminase activity in the rat hippocampus. Koomesh 2012; 13: 390-397
• 18 Vanegas H, Tortorici V. Opioidergic effects of nonopioid analgesics on the central nervous system. Cellular and molecular neurobiology 2002; 22: 655-661
• 19 Bonin RP, Labrakakis C, Eng DG. et al. Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice. Pain 2011; 152: 1317-1326
• 20 Tortorici V, Aponte Y, Acevedo H. et al. Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats. European Journal of Neuroscience 2009; 29: 1188-1196
• 21 Tortorici V, Nogueira L, Aponte Y. et al. Involvement of cholecystokinin in the opioid tolerance induced by dipyrone (metamizol) microinjections into the periaqueductal gray matter of rats. Pain 2004; 112: 113-120
• 22 Tsiklauri N, Tsagareli M. Non-opioid-induced tolerance in rats. Neurophysiology 2006; 38: 314-317
• 23 Tsiklauri N, Viatchenko-Karpinski V, Voitenko N. et al. Non-opioid tolerance in juvenile and adult rats. European Journal of Pharmacology 2010; 629: 68-72
• 24 Hernández-Delgadillo GP, Cruz SL. Endogenous opioids are involved in morphine and dipyrone analgesic potentiation in the tail flick test in rats. European journal of pharmacology 2006; 546: 54-59
• 25 Tsagareli MG, Nozadze I, Tsiklauri N. et al. Tolerance to non-opioid analgesics is opioid sensitive in the nucleus raphe magnus. Frontiers in Neuroscience 2011; 5: 92
• 26 Tang HP, Gong HR, Zhang XL. et al. Sodium salicylate enhances neural excitation via reducing GABAergic transmission in the dentate gyrus area of rat hippocampus in vivo. Hippocampus 2021; 31: 512-521
• 27 Xu H, Gong N, Chen L. et al. Sodium salicylate reduces gamma aminobutyric acid-induced current in rat spinal dorsal horn neurons. Neuroreport 2005; 16: 813-816
• 28 Fung T, Asiri YI, Wall R. et al. Variations of isovaline structure related to activity in the formalin foot assay in mice. Amino Acids 2017; 49: 1203-1213
• 29 Butt S, Ashraf F, Porter LA. et al. Sodium salicylate reduces the level of GABAB receptors in the rat’s inferior colliculus. Neuroscience 2016; 316: 41-52
• 30 Tsagareli MG, Tsiklauri N, Nozadze I. et al. Tolerance effects of non-steroidal anti-inflammatory drugs microinjected into central amygdala, periaqueductal grey, and nucleus raphe: Possible cellular mechanism. Neural regeneration research 2012; 7: 1029-1039
• 31 Mori H, Hashimoto T, Nikai T. et al. Long-Term Exposure to Morphine Induces Cross-Tolerance to Acute Antinociceptive Effect of Remifentanil on Somatic and Visceral Stimuli in Rats. Journal of Pain Research 2022; 4047-4054
• 32 Yuill MB, Zee ML, Marcus D. et al. Tolerance to the antinociceptive and hypothermic effects of morphine is mediated by multiple isoforms of c-Jun N-terminal kinase. Neuroreport 2016; 27: 392-396