Sex Differences in Antinociceptive Effects Induced by Gravity Stress in Rats


A number of studies have demonstrated that sex differentially affects responses to stress and pain. In this study, sex-related differences in pain responding were investigated in a gravity-induced analgesia model, where the effects of stressful high-gravity loading (1.5G or 2.0G for 10 min) on nociceptive behavior in male and female rats were investigated. In each rat, eight sites (nose, both forepaws, upper and lower back, both hind paws and tail) were selected to apply noxious stimuli using a von Frey-type needle stimulator. The threshold values of the withdrawal responses were measured. In order to confirm the involvement of endogenous opioids in gravity-induced antinociceptive effects, naloxone-HCl (an opioid antagonist) was used. Effective analgesic effects could be induced by strong (2.0G) gravity loading, and clear sex differences were observed. Gravity-induced analgesic effects were more effective in males than in females, indicating that males are more sensitive to stress than females judging from nociceptive modulation. Naloxone-HCl produced a more pronounced suppression of nociceptive behavior in male rats, suggesting that gravity loading may activate endogenous opioids more readily in males than in females.

Share and Cite:

M. Kimoto, J. Zeredo, Z. Nihei, H. Yamashita, K. Kaida and K. Toda, "Sex Differences in Antinociceptive Effects Induced by Gravity Stress in Rats," Journal of Behavioral and Brain Science, Vol. 3 No. 2, 2013, pp. 179-187. doi: 10.4236/jbbs.2013.32018.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] N. I. Yarushkina, “The Role of Hypothalamo-Hypophyseal-Adrenocortical System Hormones in Controlling Pain Sensitivity,” Neuroscience and Behavioral Physiology, Vol. 38, No. 8, 2008, pp. 759-766. doi:/10.1007/s11055-008-9044-z
[2] R. K. Butler and D. P. Finn, “Stress-Induced Analgesia,” Progress in Neurobiology, Vol. 88, No. 3, 2009, pp. 184-202. doi:/10.1016/j.pneurobio.2009.04.003
[3] L. Aloe, P. Tirassa and E. Alleva, “Cold Water Swimming Stress Alters Ngf and Low-Affinity Ngf Receptor Distribution in Developing Rat Brain,” Brain Research Bullutin, Vol. 33, No. 2, 1994, pp. 173-178. doi:/10.1016/0361-9230(94)90247-X
[4] R. J. Bodnar, D. D. Kelly, M. Brutus and M. Glusman, “Stress-Induced Analgesia: Neural and Hormonal Determinants,” Neuroscience Biobehavior Review, Vol. 4, No. 1, 1980, pp. 87-100. doi:/10.1016/0149-7634(80)90028-7
[5] M. N. Girardot and F. A. Holloway, “Intermittent Cold Water Stress-Analgesia in Rats: Cross-Tolerance to Morphine,” Pharmacology Biochemistry and Behavior, Vol. 20, No. 4, 1984, pp. 631-633. doi:/10.1016/0091-3057(84)90315-0
[6] R. J. Bodnar, D. D. Kelly, M. Brutus, A. Mansour and M. Glusman, “2-Deoxy-D-Glucose-Induced Decrements in Operant and Ref-lex Pain Thresholds,” Pharmacology Biochemistry and Behavior, Vol. 9, No. 4, 1978, pp. 543549. doi:/10.1016/0091-3057(78)90056-4
[7] R. McGivern, C. Berka, G. G. Berntson, J. M. Walker and C. A. Sandman, “Effect of Naloxone on Analgesia Induced by Food Deprivation,” Life Science, Vol. 25, No. 10, 1979, pp. 885-888. doi:/10.1016/0024-3205(79)90547-2
[8] H. Akil, J. Madden, R. L. Patrick and J. D. Barchas, “Stress-Induced Increase in Endogenous Opiate Peptides: Concurrent Analgesia and Its Partial Reversal by Naloxone,” In: H. W. Kosterlitz, Ed., Opiates and Endogenous Opioid Peptides, North-Holland Publishing Co., Amsterdam, 1976, pp. 63-70.
[9] J. W. Lewis, J. T. Cannon and J. C. Liebeskind, “Opioid and Nonopioid Me-chanisms of Stress Analgesia,” Science, Vol. 208, No. 4444, 1980, pp. 623-625. doi:/10.1126/science.7367889
[10] W. R. Crowley, J. F. Rodriguez-Sierra and B. R. Komisaruk, “Analgesia Induced by Vaginal Stimulation in Rats Is Apparently Independent of a Morphine-Sensitive Process,” Psychopharmacology (Berl), Vol. 54, No. 3, 1977, pp. 223-225. doi:/10.1007/BF00426567
[11] P. Nishith, M. G. Griffin and T. L. Poth, “Stress-Induced Analgesia: Prediction of Posttraumatic Stress Symptoms in Battered Versus Nonbattered Women,” Biological Psychiatry, Vol. 51, No. 11, 2002, pp. 867-874. doi:/10.1016/S0006-3223(01)01346-4
[12] L. Knudsen and P. D. Drummond, “Cold-Induced Limb Pain Decreases Sensitivity to Pressure-Pain Sensations in the Ipsilateral Forehead,” European Journal of Pain, Vol. 13, No. 10, 2009, pp. 1023-1029. doi:/10.1016/j.ejpain.2008.12.005
[13] P. M. Aslaksen and M. A. Flaten, “The Roles of Physiological and Subjective Stress in the Effectiveness of a Placebo on Experimentally Induced Pain,” Psychosomatic Medicine, Vol. 70, No. 7, 2008, pp. 811-818. doi:/10.1097/PSY.0b013e31818105ed
[14] Y. Kawauchi, J. L. Zeredo, Y. Takeuchi, M. Kimoto, Y. Kumei, K. Makita and K. Toda, “Nociceptive Threshold Can Be Changed by Gravity Stimulation in Rats,” Stress and Health, Vol. 20, No. 1, 2004, pp. 45-50. doi:/10.1002/smi.990
[15] Y. Kumei, R. Shimokawa, M. Kimoto, Y. Kawauchi, H. Shimokawa, K. Makita, K. Ohya and K. Toda, “Gravity Stress Elevates the Nociceptive Threshold Level with Immunohistochemical Changes in the Rat Brain,” Acta Astronaut, Vol. 49, No. 3-10, 2001, pp. 381-390.
[16] K. J. Kovacs, “Measurement of Immediate-Early Gene Activation-C-Fos and Beyond,” Journal of Neuroendocrinology, Vol. 20, No. 6, 2008, pp. 665-672. doi:/10.1111/j.1365-2826.2008.01734.x
[17] A. Sainsbury and L. Zhang, “Role of the Arcuate Nucleus of the Hypothalamus in Regulation of Body Weight during Energy Deficit,” Molecular Cell Endocrinology, Vol. 316, No. 2, 2010, pp. 109-119. doi:/10.1016/j.mce.2009.09.025
[18] L. Macho, R. Kvetnansky, M. Fickova, I. A. Popova and A. Grigoriev, “Effects of Exposure to Space Flight on Endocrine Regulations in Experimental Animals,” Endocrine Regulations, Vol. 35, No. 2, 2001, pp. 101-114.
[19] R. M. Craft, J. S. Mogil and A. M. Aloisi, “Sex Differences in Pain and Analgesia: The Role of Gonadal Hormones,” European Journal of Pain, Vol. 8, No. 5, 2004, pp. 397-411. doi:/10.1016/j.ejpain.2004.01.003
[20] W. F. Sternberg and J. C. Liebeskind, “The Analgesic Response to Stress: Genetic and Gender Considerations,” European Journal of Anaesthesiology—Supplement, Vol. 10, No. 1995, pp. 14-17.
[21] G. J. Ter Horst, R. Wichmann, M. Gerrits, C. Westenbroek and Y. Lin, “Sex Differences in Stress Responses: Focus on Ovarian Hormones,” Physiological Behaviour, Vol. 97, No. 2, 2009, pp. 239-249. doi:/10.1016/j.physbeh.2009.02.036
[22] M. M. Faraday, K. H. Blakeman and N. E. Grunberg, “Strain and Sex Alter Effects of Stress and Nicotine on Feeding, Body Weight, and Hpa Axis Hormones,” Pharmacology Biochemistry and Behavior, Vol. 80, No. 4, 2005, pp. 577-589. doi:/10.1016/j.pbb.2005.01.015
[23] D. E. Pankevich and T. L. Bale, “Stress and Sex Influences on Food-Seeking Behaviors,” Obesity (Silver Spring), Vol. 16, No. 7, 2008, pp. 1539-1544. doi:/10.1038/oby.2008.221
[24] M. T. Romero and R. J. Bodnar, “Gender Differences in Two Forms of Cold-Water Swim Analgesia,” Physiological Behaviour, Vol. 37, No. 6, 1986, pp. 893-897. doi:/10.1016/S0031-9384(86)80009-9
[25] L. Bartos, “Vaginal Impedance Measurement Used for Mating in the Rat,” Lab Animal, Vol. 11, No. 1, 1977, pp. 53-55. doi:/10.1258/002367777780959148
[26] C. Chotiwat, E. W. Kelso and R. B. Harris, “The Effects of Repeated Restraint Stress on Energy Balance and Behavior of Mice with Selective Deletion of Crf Receptors,” Stress, Vol. 13, No. 3, 2010, pp. 203-213. doi:/10.3109/10253890903207527
[27] H. Imbe, K. Okamoto, T. Donishi, E. Senba and A. Kimura, “Involvement of Descending Facilitation from the Rostral Ventromedial Medulla in the Enhancement of Formalin-Evoked Nocifensive Behavior Following Repeated Forced Swim Stress,” Brain Research, Vol. 1329, No. 2010, pp. 103-112. doi:/10.1016/j.brainres.2010.03.006
[28] K. Toda, H. Suda, M. Ichioka and A. Iriki, “Local Electrical Stimulation: Effective Needling Points for Suppressing Jaw Opening Reflex in Rat,” Pain, Vol. 9, No. 2, 1980, pp. 199-207. doi:/10.1016/0304-3959(80)90007-X
[29] K. J. Berkley, “Sex Differences in Pain,” Behavior Brain Science, Vol. 20, No. 3, 1997, pp. 371-380. doi:/10.1017/S0140525X97221485
[30] R. B. Fillingim, “Sex, Gender, and Pain: Women and Men Really Are Different,” Current Review Pain, Vol. 4, No. 1, 2000, pp. 24-30. doi:/10.1007/s11916-000-0006-6
[31] R. B. Fillingim and W. Maixner, “Gender Differences in the Responses to Noxious Stimuli,” Pain Forum, Vol. 4, No. 4, 1995, pp. 209-221.
[32] J. L. Riley, M. E. Robinson, E. A. Wise, C. D. Myers and R. B. Fillingim, “Sex Differences in the Perception of Noxious Experimental Stimuli: A Meta-Analysis,” Pain, Vol. 74, No. 2-3, 1998, pp. 181-187. doi:/10.1016/S0304-3959(97)00199-1
[33] R. B. Fillingim, C. D. King, M. C. Ribeiro-Dasilva, B. Rahim-Williams and J. L. Riley, “Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings,” Journal of Pain, Vol. 10, No. 5, 2009, pp. 447-485. doi:/10.1016/j.jpain.2008.12.001
[34] J. A. Hashmi and K. D. Davis, “Women Experience Greater Heat Pain Adaptation and Habituation Than Men,” Pain, Vol. 145, No. 3, 2009, pp. 350-357. doi:/10.1016/j.pain.2009.07.002
[35] S. G. Khasar, F. J. Miao, R. W. Gear, P. G. Green and J. D. Levine, “Vagal Modulation of Bradykinin-Induced Mechanical Hyperalgesia in the Female Rat,” Journal of Pain, Vol. 4, No. 5, 2003, pp. 278-283. doi:/10.1016/S1526-5900(03)00631-X
[36] C. J. Vierck, A. J. Acosta-Rua, H. L. Rossi and J. K. Neubert, “Sex Differences in Thermal Pain Sensitivity and Sympathetic Reactivity for Two Strains of Rat,” Journal of Pain, Vol. 9, No. 8, 2008, pp. 739-749. doi:/10.1016/j.jpain.2008.03.008
[37] A. J. Devall and T. A. Lovick, “Differential Activation of the Periaqueductal Gray by Mild Anxiogenic Stress at Different Stages of the Estrous Cycle in Female Rats,” Neuropsychopharmacology, Vol. 35, No. 5, 2010, pp. 11741185. doi:/10.1038/npp.2009.222
[38] M. Frot, J. S. Feine and M. C. Bushnell, “Sex Differences in Pain Perception and Anxiety. A Psychophysical Study with Topical Capsaicin,” Pain, Vol. 108, No. 3, 2004, pp. 230-236. doi:/10.1016/j.pain.2003.11.017
[39] J. M. Tall and T. Crisp, “Effects of Gender and Gonadal Hormones on Nociceptive Responses to Intraplantar Carrageenan in the Rat,” Neuroscience Letters, Vol. 354, No. 3, 2004, pp. 239-241. doi:/10.1016/j.neulet.2003.09.081
[40] M. Kimoto, J. L. Zeredo and K. Toda, “Irritant-Drinking Behaviour Can Be Modified by Gravity-Stress Loaded in Developing but Not in Adult Rats,” Stress and Health, Vol. 27, No. 1, 2011, pp. 34-41. doi:/10.1002/smi.1317
[41] M. Lafrance, G. Roussy, K. Belleville, H. Maeno, N. Beaudet, K. Wada and P. Sarret, “Involvement of Nts2 Receptors in Stress-Induced Analgesia,” Neuroscience, Vol. 166, No. 2, 2010, pp. 639-652. doi:/10.1016/j.neuroscience.2009.12.042
[42] L. R. Watkins, D. A. Cobelli, P. Faris, M. D. Aceto and D. J. Mayer, “Opiate Vs Non-Opiate Footshock-Induced Analgesia (Fsia): The Body Region Shocked Is a Critical Factor,” Brain Research, Vol. 242, No. 2, 1982, pp. 299-308. doi:/10.1016/0006-8993(82)90313-4
[43] J. McBeth, Y. H. Chiu, A. J. Silman, D. Ray, R. Morriss, C. Dickens, A. Gupta and G. J. Macfarlane, “Hypothalamic-Pituitary-Adrenal Stress Axis Function and the Relationship with Chronic Widespread Pain and Its Antecedents,” Arthritis Research Therapy, Vol. 7, No. 5, 2005, pp. R992-R1000. doi:/10.1186/ar1772
[44] V. T. Martin, “Ovarian Hormones and Pain Response: A Review of Clinical and Basic Science Studies,” Gender Medicine, Vol. 6, No. 2009, pp. 168-192.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.