Abstract
Gender difference in the antinociceptive effect of tramadol and gabapentin (alone or in combination) were investigated in mice. For investigation of acute antinociceptive effect, tramadol and gabapentin were administered to mice by intraperitoneal injection and per os, respectively, and antinociceptive activity was measured by the tail-flick test 30 min after drug administration. For investigation of the development of antinociceptive tolerance to analgesics, mice were injected with tramadol (60 mg/kg), alone or in combination with gabapentin (75 mg/kg), twice daily for seven consecutive days and the tail-flicks were tested on experimental days 1, 3, 5 and 7. Results showed there was a lower ED50 value of tramadol antinociception in males than in females, indicating that females were less sensitive to the drug. Gabapentin produces a limited antinociception in both males and females. The combination of gabapentin and tramadol produced synergistic effect without gender difference. Repeated administration of tramadol produced antinociceptive tolerance in both genders. Gabapentin produced synergistic effect in tramadol-tolerant mice and repeated administration of gabapentin did not alter the synergistic effect in tramadol-tolerant mice. Because females show a higher overall prevalence of pain and less sensitivity to opioids, our finding may suggest a clinical significance of combined use of the two drugs.
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References
Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–923
Cossmann M, Kohnen C, Langford R, McCartney C (1997) Tolerance and safety of tramadol use. Results of international studies and data from drug surveillance. Drugs 53(Suppl 2):50–62
Tai Q, Kirshblum S, Chen B, Millis S, Johnston M, DeLisa JA (2002) Gabapentin in the treatment of neuropathic pain after spinal cord injury: a prospective, randomized, double-blind, crossover trial. J Spinal Cord Med 25:100–105
Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK (2004) Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anaesth 51:358–363
Hansen C, Gilron I, Hong M (2004) The effects of intrathecal gabapentin on spinal morphine tolerance in the rat tail-flick and paw pressure tests. Anesth Analg 99:1180–1184
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL (2005) Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 352:1324–1334
Meymandi MS, Sepehri G, Mobasher M (2006) Gabapentin enhances the analgesic response to morphine in acute model of pain in male rats. Pharmacol Biochem Behav 85:185–189
Cepeda MS, Carr DB (2003) Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg 97:1464–1468
Craft RM (2003) Sex differences in opioid analgesia: from mouse to man. Clin J Pain 19:175–186
Wang X, Traub RJ, Murphy AZ (2006) Persistent pain model reveals sex difference in morphine potency. Am J Physiol Regul Integr Comp Physiol 291:R300–R306
Cook CD, Barrett AC, Roach EL, Bowman JR, Picker MJ (2000) Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the mu opioid receptor. Psychopharmacology (Berl) 150:430–442
Craft RM, Tseng AH, McNiel DM, Furness MS, Rice KC (2001) Receptor-selective antagonism of opioid antinociception in female versus male rats. Behav Pharmacol 12:591–602
Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN (1998) Mu opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 54:321–326
D’amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharm Exp Ther 72:74–79
Kavaliers M, Innes D (1987) Sex differences in magnetic field inhibition of morphine-induced responses of wild deer mice, Peromyscus maniculatus triangularis. Physiol Behav 40:559–562
Candido J, Lutfy K, Billings B, Sierra V, Duttaroy A, Inturrisi CE, Yoburn BC (1992) Effect of adrenal and sex hormones on opioid analgesia and opioid receptor regulation. Pharmacol Biochem Behav 42:685–692
Bernal SA, Morgan MM, Craft RM (2007) PAG mu opioid receptor activation underlies sex differences in morphine antinociception. Behav Brain Res 177:126–133
Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285
Kayser V, Besson JM, Guilbaud G (1991) Effects of the analgesic agent tramadol in normal and arthritic rats: comparison with the effects of different opioids, including tolerance and cross-tolerance to morphine. Eur J Pharmacol 195:37–45
Miranda HF, Pinardi G (1998) Antinociception, tolerance, and physical dependence comparison between morphine and tramadol. Pharmacol Biochem Behav 61:357–360
Valle M, Garrido MJ, Pavon JM, Calvo R, Troconiz IF (2000) Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (−)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther 293:646–653
Ming XY, Wang W, Han JS, Luo F (2005) Tramadol and dihydroetorphine produce synergistic analgesic effect and postpones acute opiate tolerance in rats. Acta Physiol Sinica 57:696–704
Von Zastrow M, Svingos A, Haberstock-Debic H, Evans C (2003) Regulated endocytosis of opioid receptors: cellular mechanisms and proposed roles in physiological adaptation to opiate drugs. Curr Opin Neurobiol 13:348–353
Riley JL, Robinson ME, Wise EA, Price DD (1999) A meta-analytic review of pain perception across the menstrual cycle. Pain 81:225–235
Kest B, Sarton E, Dahan A (2000) Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology 93:539–247
Barsky AJ, Peekna HM, Borus JF (2001) Somatic symptom reporting in women and men. J Gen Intern Med 16:266–275
Kest B, Wilson S, Mogil J (1999) Sex differences in supraspinal morphine analgesia are dependent on genotype. J Pharmacol Exp Ther 289:1370–1375
Negus SS, Mello NK (1999) Opioid antinociception in ovariectomized monkeys: comparison with antinociception in males and effects of estradiol replacement. J Pharmacol Exp Ther 290:1132–1140
Sindrup SH, Jensen TS (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400
Goldlust A, Su TZ, Welty DF, Taylor CP, Oxender DL (1995) Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 22:1–11
Su TZ, Lunney E, Campbell G, Oxender DL (1995) Transport of gabapentin, a γ-amino acid drug, by system l α-amino acid transporters: a comparative study in astrocytes, synaptosomes and CHO cells. J Neurochem 64:2125–2131
Cheng JK, Chiou (2006) Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci 100:471–486
Neurontin® (2007) http://www.neurontin-side-effects.net/
Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the subunit of a calcium channel. J Biol Chem 271:5768–5776
Brown JP, Gee NS (1998) Cloning and deletion mutagenesis of the alpha2 delta calcium channel subunit from porcine cerebral cortex. Expression of a soluble form of the protein that retains [3H] gabapentin binding activity. J Biol Chem 273:25458–25465
Dooley DJ, Mieske CA, Borosky SA (2000) Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 280:107–110
Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Clusmann H, Gothert M (2002) Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 42:229–236
Errante LD, Petroff OA (2003) Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure 12:300–306
Chow LH, Huang EY, Ho ST, Lee TY, Tao PL (2004) Dextromethorphan potentiates morphine antinociception at the spinal level in rats. Can J Anaesth 51:905–910
Martin VT, Behbehani M (2006) Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part I. Heaache 46:3–23
Cairns BE, Hu JW, Arendt-Nielsen L, Sessle BJ, Svensson P (2001) Sex-related differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol 86:782–791
Cairns BE, Sessle BJ, Hu JW (2001) Characteristics of glutamate-evoked temporomandibular joint afferent activity in the rat. J Neurophysiol 85:2446–2454
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The authors gratefully thank Dr. Whitney Wiltshire, Dr. Ike Eriator, and Mrs. Marsha Manuel for their careful proofreading of the manuscript.
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Dai, X., Brunson, C.D., Rockhold, R.W. et al. Gender differences in the antinociceptive effect of tramadol, alone or in combination with gabapentin, in mice. J Biomed Sci 15, 645–651 (2008). https://doi.org/10.1007/s11373-008-9252-0
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DOI: https://doi.org/10.1007/s11373-008-9252-0