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Lycopene and ketotifen potentiates the anti-hyperalgesic effect of gabapentin in PSNL-induced neuropathic pain in wistar rats

Nischal Tyagi


The present study is designed to investigate the involvement of antioxidant mechanism and role of mast cells in pathophysiology of neuropathic pain induced by partial sciatic nerve ligation. The effect was evaluated by assessing various behavioural parameters (thermal hyperalgesia, cold hyperalgesia), biochemical parameters (lipid peroxidation, reduced glutathione, superoxide dismutase and catalase). Partial Sciatic nerve ligation (PSNL) significantly caused thermal hyperalgesia, cold hyperalgesia and oxidative damage as compared to normal and sham and group. Upon daily administration of combination of lycopene (50 mg/kg), ketotifen (10mg/kg) and gabapentin (100 mg/kg) considerably reversed hyperalgesia, cold hyperalgesia and also attenuated oxidative stress when compared to PSNL group. The results indicated that combination lycopene, ketotifen and gabapentin exhibited a potentiating effect in neuropathic pain by inhibiting degranulation of mast cells and also by reducing oxidative stress.


lycopene, ketotifen, gabapentin, degranulation, hyperalgesia.

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Galli, SJ et al., Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol, 23, (2005), 749–86.

Metcalfe DD et al., Mast cells. Physiol. Rev,77, (1997), 1033–79.

Olsson Y. Degranulation of mast cells in peripheral nerve injuries. Acta Neurol Scand, 43, (1967), 365–74.

Zuo Y et al., Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells. Pain, 105, (2003), 467–79.

McLean PG et al., Association between kinin B (1) receptor expression and leukocyte trafficking across mouse mesenteric postcapillary venules. J Exp Med, 192, (2000), 367–80.

Sawynok J et al., Involvement of mast cells, sensory afferents and sympathetic mechanisms in paw oedema induced by adenosine A (1) and A (2B/3) receptor agonists. Eur J Pharmacol, 395, (2000), 47–50.

Kuhad A, Sharma S, Chopra K. Lycopene attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. European journal of pain, 12, (2008), 624-632.

Yanai K et al., Roles of histamine receptors in pain perception: a study using receptors gene knockout mice. Nihon Yakurigaku Zasshi, 122, (2003), 391-99.

Mobarakeh JI et al., Role of histamine H (1) receptor in pain perception: a study of the receptor gene knockout mice. Eur J Pharmacol, 391, (2000), 81-89.

Cowart MD et al., Rotationally constrained 2, 4-diamino-5, 6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models. J Med Chem, 51, (2008), 6547-57.

Kamo A. et al., Histamine H (4) receptor antagonists ineffective against itch and skin inflammation in atopic dermatitis mouse model. J Invest Dermatol, 134, (2014), 546-48.

Cowden J.M. et al., The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis. Ann Rheum Dis, 73, (2014), 600-8.

Coruzzi G. et al., Anti-inflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol, 563, (2007), 240-44.

Klooker T.K. et al., The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irriFigure bowel syndrome. Gut, 59, (2010), 1213-21.

Serna H et al., Mast cell stabilizer ketotifen [4-(1-methyl-4-piperidylidene)-4h-benzo [4,5] cyclohepta[1,2-b]thiophen-10(9H)-one fumarate] prevents mucosal mast cell hyperplasia and intestinal dysmotility in experimental Trichinella spiralis inflammation in the rat. J Pharmacol Exp Ther, 319, (2003), 1104-11.

Seltzer Z et al., A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain, 43, (1990), 205–18.

Bennett GJ, Xie YK. A peripheral mononeuropathy in rats that produces disorder of pain sensation like those seen in man. Pain, 33, (1998), 87-107.

Patan SF et al., Mast cell inhibition by ketotifen reduces splanchic inflammatory response in a portal hypertension model in rats. Exp and. Tox Path, 60, (2008), 347-55.

Fox A. et al., Comparative activity of anti-convulsant oxcarbazepine, carbamazepine, lamotrigine, and gabapentin in a model of neuropathic pain in rat and guinea pig. Pain, 105, (2003), 355-62.

Lambiase A et al., Multiple action agents and the eye: do they really stabilize mast cells? Curr Opin Allergy. Clin Immunol, 9, (2009), 454–65.

Kennedy PG et al., Latent Varicella-zoster virus in human dorsal root ganglia. Virol, 258, (1999), 451–54.

Fleetwood-Walker SM et al., Behavioural changes in the rat following infection with varicella-zoster virus. J Gen Virol, 80, (1999), 2433–36.

Ohkawa H et al., Assay of lipid peroxides in animal tissues by thiobarbituric acid reaction. Biochem, 95, (1979), 351 – 58.

Kukkar A et al., Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res, 36, (2013), 237–51.

Lowry OH et al., Protein measurement with the folin phenol reagent. J Biol Chem, 193, (1951), 265-75.

Ellman GH. Tissue sulfhydryl groups. Arch. Biochem Biophys, 82, (1959), 70-77.

Marklund S, Marklund G. Involvement of the Superoxide Anion Radical in the Autoxidation of Pyrogallol and a Convenient Assay for Superoxide Dismutase. Eur J Biochem, 47, (1974), 469-74.

Clairborne A. Catalase activity in: greenwald ra crs handbook of methods in oxygen radical research boca raton, CRS press, (1985), 283-84.

Yu CX et al., Selective MT (2) melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neurosci Lett 2000, 282, (2000), 161-164.

Scadding J. Neuropathic pain review. Advances in Clinical Neuroscience and Rehabilitation, 3, (2003), 814.

Sorkin LS et al., Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience, 81, (1997), 255–62.

S. Beniczky, Tajti J, E Timea varga, L vecsei. Evidence-based pharmacological treatment of neuropathic pain syndromes. J. of neural transmission, 112, (2005), 735-749.

Karmeli F et al., Gastric mucosal damage is mediated by substance P and prevented by ketotifen. Gastroenterology, 100, (1991), 1206-16.



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