Preventive effects of progesterone against neuropathic pain responses in a rat model of chronic constriction injury

authors:

avatar Morteza Jarrahi , avatar Roya Hasani , avatar A. li Rashidy-Pour , avatar Hossein ali Safakhah , *

Koomesh: Vol.21, issue 1; 164-170
published online: March 01, 2019
article type: Research Article
received: May 07, 2018
accepted: October 01, 2018

how to cite: Jarrahi M, Hasani R, Rashidy-Pour A L, Safakhah H A. Preventive effects of progesterone against neuropathic pain responses in a rat model of chronic constriction injury. koomesh. 2019;21(1):e153053. 

Abstract

Introduction: Neuropathic pain is a chronic pain that results from damage to the central nervous system and also environment. Neuropathic pain is important for general health and approximately 6% of the adult population is affected worldwide. Despite the therapeutic choices, treatment for neuropathic pain is facing challenges. An experimental model that is very close to human neuropathic model is the chronic constriction injury (CCI) model.  Progesterone (PROG) is one of the most potent anti-inflammatory and anti-inflammatory neurostimulants, and GABA-A receptor palys an important role in mediating the biological effects of PROG. In this study, the effects of PROG on behavioral responses of pain in the neuropathic pain model of CCI, and the possible role of GABA-A receptor in its effect were investigated in rats. Materials and Methods:  70 male Wistar rats were used in 7 groups (n = 10). First, neuropathic pain was induced by the CCI method in the respective groups. Following CCI, PROG (6 mg/kg) and or the GABA-A receptor antagonist bicuculin (0.5 or 2 mg/kg) or vehicle were administered daily until day 13 post-CCI. On days 14 and 27, the behavioural tests including mechanical allodynia and thermal hyperalgesia were done. Results: Daily injections of PROG PROG for 12 days prevented the mechanical allodynia and thermal hyperalgesia following CCI and this effect was blocked the bicuculin pretreatment. Conclusion: The findings of this study showed that treatment with progesterone may prevent the development of peripheral neuropathy, at least in part, via GABA-A receptors.

References

  • 1.

    Devor M. Neuropathic pain: what do we do with all these theories? ActaAnaesthesioloScand 2001; 45: 1121-1127.

  • 2.

    Geis C, Geuss E, Sommer C, Schmidt HH, Kleinschnitz C. NOX4 is an early initiator of neuropathic pain. ExpNeurol 2017; 288: 94-103.

  • 3.

    Mellon SH, Griffin LD. Neurosteroids: biochemistry and clinical significance. Trends EndocrinolMetab2002; 13: 35-43.

  • 4.

    Pathirathna S, Brimelow BC, Jagodic MM, Krishnan K, Jiang X, Zorumski CF, Mennerick S, Covey DF, Todorovic SM, Jevtovic-Todorovic V. New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5-reduced neuroactive steroids. Pain 2005; 114: 429-443.

  • 5.

    Carlton SM, Hargett GL, Coggeshall RE. Plasticity in -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits in the rat dorsal horn followingdeafferentation.NeurLett 1998; 242: 21-24.

  • 6.

    De Nicola AF, Labombarda F, Deniselle MC, Gonzalez SL, Garay L, Meyer M, et al. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration. Front Neuroendocrinol2009; 30: 173-187.

  • 7.

    Coronel MF, Labombarda F, Villar MJ, De Nicola AF, Gonzlez SL. Progesterone prevents allodynia after experimental spinal cord injury. J Pain 2011; 12: 71-83.

  • 8.

    Azcoitia I, Leonelli E, Magnaghi V, Veiga S, Garcia-Segura LM, Melcangi RC. Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats. Neurobiol Aging 2003; 24: 853-860.

  • 9.

    Krause Neto W, Silva WdA, Ciena AP, Nucci RAB, Anaruma CA, Gama EF. Effects of strength training and anabolic steroid in the peripheral nerve and skeletal muscle morphology of aged rats.Front Aging Neurosci2017; 9: 205.

  • 10.

    Gintzler AR, Liu NH. The maternal spinal cord: biochemical and physiological correlates of steroid-activated antinociceptive processes. Prog Brain Res2001;133: 83-97.

  • 11.

    Guennoun R, Labombarda F, Deniselle MG, Liere P, De Nicola AF, Schumacher M. Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection. J Steroid BiochemMolBiol 2015; 146: 48-61.

  • 12.

    De Nicola AF, Deniselle G, Garay L, Meyer M, GargiuloMonachelli G, Guennoun R, Schumacher M, Carreras MC, Poderoso JJ. Progesterone protective effects in neurodegeneration and neuroinflammation.J Neuroendocrinol2013; 25: 1095-1103.

  • 13.

    Lee JCT. Neuroprotectiveeffect of fluocinoloneacetonide on mitochondria in paclitaxel-induced peripheral neuropathy: National University of Singapore (Singapore); 2017.

  • 14.

    Bennett GJ, Xie YK.A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.Pain 1988; 33: 87-107.

  • 15.

    Safakhah HA, Taghavi T, Rashidy-Pour A, Vafaei AA, Sokhanvar M, Mohebbi N, Rezaei-Tavirani M. Effects of saffron (Crocus sativus L.) stigma extract and its active constituent crocin on neuropathic pain responses in a rat model of chronic constriction injury. Iran J Pharm Res 2016; 15: 253. (Persian).

  • 16.

    Safakhah HA, Kor NM, Bazargani A, Bandegi AR, Pourbadie HG, Khoshkholgh-Sima B, Ghanbari A. Forced exercise attenuates neuropathic pain in chronic constriction injury of male rat: an investigation of oxidative stress and inflammation. J Pain Res 2017; 10: 1457. (Persian).

  • 17.

    Castelnovo LF, Magnaghi V, Thomas P. Expression of membrane progesterone receptors (mPRs) in rat peripheral glial cell membranes and their potential role in the modulation of cell migration and protein expression. Steroids 2017.

  • 18.

    Castelnovo L. Molecular basis for the development of innovative therapies for peripheral neuropathies treatment: role and cross-regulation of the GABAergic system and neuroactive steroids. 2017.

  • 19.

    Melcangi RC, GiattiS, Calabrese D, Pesaresi M, Cermenati G, Mitro N, et al. Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions. ProgNeurobiol2014; 113: 56-69.

  • 20.

    Onodera Y, Kanao-Kanda M, Kanda H, Sasakawa T, Iwasaki H, Kunisawa T. Pregnancy suppresses neuropathic pain induced by chronic constriction injury in rats through the inhibition of TNF-. J Pain Res 2017; 10: 567.

  • 21.

    Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Pelletier G, Vaudry H. Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 1999; 51: 63-82.

  • 22.

    Melcangi RC, Garcia-Segura LM. Therapeutic approaches to peripheral neuropathy based on neuroactive steroids. Expert Rev Neurother 2006; 6: 1121-1125.

  • 23.

    Lambert JJ, Cooper MA, Simmons RD, Weir CJ, Belelli D. Neurosteroids: endogenous allosteric modulators of GABAA receptors. Psychoneuroendocrinology 2009; 34: S48-S58.

  • 24.

    Kaur P, Jodhka PK, Underwood WA, Bowles CA, de Fiebre NC, de Fiebre CM, Singh M. Progesterone increases brainderived neuroptrophic factor expression and protects against glutamate toxicity in a mitogenactivated protein kinaseand phosphoinositide3 kinasedependent manner in cerebral cortical explants. J Neurosci Res2007; 85: 2441-2449.

  • 25.

    Naik AK, Latham JR, Obradovic A, Jevtovic-Todorovic V. Dorsal root ganglion application of muscimol prevents hyperalgesia and stimulates myelin protein expression after sciatic nerve injury in rats. AnesthAnalg2012; 114: 674-682.

  • 26.

    Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413: 203.

  • 27.

    Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, et al. Progesterone synthesis and myelin formation by Schwann cells. Science 1995; 268: 1500-1503.

  • 28.

    Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura L, et al. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 2007; 144: 1293-1304.

  • 29.

    Wang LX, Wang ZJ. Animal and cellular models of chronic pain.Adv Drug Deliv Rev 2003; 55: 949-965.

  • 30.

    LaCroix-Fralish ML, Tawfik VL, DeLeo JA. The organizational and activational effects of sex hormones on tactile and thermal hypersensitivity following lumbar nerve root injury in male and female rats. Pain 2005; 114: 71-80.

  • 31.

    Safakhah HA, Taghavi T, Rashidy-Pour A, et al. Effects of saffron (Crocus sativus L.) stigma extract and its active constituent crocin on neuropathic pain responses in a rat model of chronic constriction injury. Iran J Pharm Res 2016;15: 253-261.(Persian).