Atipamezole changes the antinociceptive effects of butorphanol after medetomidine–ketamine anaesthesia in rats



      To investigate the effects of atipamezole administered before butorphanol, on tail-flick latency (TFL) and also following medetomidine–ketamine anaesthesia in rats.

      Study design

      Prospective, randomized experimental study.


      Thirty-four adult male Sprague–Dawley rats weighing 260–390 g.


      TFL in 50 °C water was used to measure antinociception. In the first experiment, rats received saline (n = 5) or atipamezole (n = 5) followed by butorphanol treatments. In the second experiment, three groups of rats received saline (n = 8), atipamezole (n = 8) or atimpamezole (n = 8) followed by butorphanol 60 minutes after medetomidine–ketamine administration.


      In the first experiment, butorphanol significantly increased TFL compared to baseline. Atipamezole significantly decreased this effect. In the second experiment, TFL was significantly increased after recovery from medetomidine–ketamine anaesthesia compared to baseline. This was almost completely blocked by atipamezole. Atipamezole with butorphanol after recovery from the anaesthesia significantly reduced TFL compared to saline but still significantly increased TFL compared to the baseline.

      Conclusion and clinical relevance

      Atipamezole attenuated the analgesic effects of butorphanol. When postoperative atipamezole is used to hasten recovery from anaesthesia in rats, it may interfere with the postoperative analgesic effect of butorphanol.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Veterinary Anaesthesia and Analgesia
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Baker AK
        • Hoffmann VL
        • Meert TF
        Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain.
        Pharmacol Biochem Behav. 2002; 74: 73-86
        • Cooper DM
        • Hoffman W
        • Wheat N
        • et al.
        Duration of effects on clinical parameters and referred hyperalgesia in rats after abdominal surgery and multiple doses of analgesic.
        Comp Med. 2005; 55: 344-353
        • Crisp T
        • Perrotti JM
        • Smith DL
        • et al.
        The local monoaminergic dependency of spinal ketamine.
        Eur J Pharmacol. 1991; 194: 167-172
        • Cruz JI
        • Loste JM
        • Burzaco OH
        Observations on the use of medetomidine/ketamine and its reversal with atipamezole for chemical restraint in the mouse.
        Lab Anim. 1998; 32: 18-22
        • Fields HL
        • Heinricher MM
        • Mason P
        Neurotransmitters in nociceptive modulatory circuits.
        Annu Rev Neurosci. 1991; 14: 219-245
        • Gades NM
        • Danneman PJ
        • Wixson SK
        • et al.
        The magnitude and duration of the analgesic effect of morphine, butorphanol, and buprenorphine in rats and mice.
        Contemp Top Lab Anim Sci. 2000; 39: 8-13
        • Garcia-Pereira FL
        • Greene SA
        • Keegan RD
        • et al.
        Effects of intravenous butorphanol on cardiopulmonary function in isoflurane-anesthetized alpacas.
        Vet Anaesth Analg. 2007; 34: 269-274
        • Guyenet PG
        • Stornetta RL
        • Riley T
        • et al.
        Alpha 2A-adrenergic receptors are present in lower brainstem catecholaminergic and serotonergic neurons innervating spinal cord.
        Brain Res. 1994; 638: 285-294
        • Hedenqvist P
        • Roughan JV
        • Flecknell PA
        Effects of repeated anaesthesia with ketamine/medetomidine and of pre-anaesthetic administration of buprenorphine in rats.
        Lab Anim. 2000; 34: 207-211
        • Hedenqvist P
        • Roughan JV
        • Flecknell PA
        Sufentanil and medetomidine anaesthesia in the rat and its reversal with atipamezole and butorphanol.
        Lab Anim. 2000; 34: 244-251
        • Hylden JL
        • Thomas DA
        • Iadarola MJ
        • et al.
        Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia: possible involvement of noradrenergic mechanisms.
        Eur J Pharmacol. 1991; 194: 135-143
        • Jang HS
        • Choi HS
        • Lee SH
        • et al.
        Evaluation of the anaesthetic effects of medetomidine and ketamine in rats and their reversal with atipamezole.
        Vet Anaesth Analg. 2009; 36: 319-327
        • Johnson JA
        • Robertson SA
        • Pypendop BH
        Antinociceptive effects of butorphanol, buprenorphine, or both, administered intramuscularly in cats.
        Am J Vet Res. 2007; 68: 699-703
        • Jones CK
        • Peters SC
        • Shannon HE
        Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents.
        J Pharmacol Exp Ther. 2005; 312: 726-732
        • Kauppila T
        • Jyväsjärvi E
        • Hämäläinen MM
        • et al.
        The effect of a selective alpha2-adrenoceptor antagonist on pain behavior of the rat varies, depending on experimental parameters.
        Pharmacol Biochem Behav. 1998; 59: 477-485
        • Kawamata T
        • Omote K
        • Sonoda H
        • et al.
        Analgesic mechanisms of ketamine in the presence and absence of peripheral inflammation.
        Anesthesiology. 2000; 93: 520-528
        • Kim MS
        • Jeong SM
        • Park JH
        • et al.
        Reversal of medetomidine–ketamine combination anesthesia in rabbits by atipamezole.
        Exp Anim. 2004; 53: 423-428
        • Kingery WS
        • Agashe GS
        • Guo TZ
        • et al.
        Isoflurane and nociception: spinal alpha2A adrenoceptors mediate antinociception while supraspinal alpha1 adrenoceptors mediate pronociception.
        Anesthesiology. 2002; 96: 367-374
        • Ko JC
        • Fox SM
        • Mandsager RE
        Sedative and cardiorespiratory effects of medetomidine, medetomidine-butorphanol, and medetomidine–ketamine in dogs.
        J Am Vet Med Assoc. 2000; 216: 1578-1583
        • Liles JH
        • Flecknell PA
        The effects of buprenorphine, nalbuphine and butorphanol alone or following halothane anaesthesia on food and water consumption and locomotor movement in rats.
        Lab Anim. 1992; 26: 180-189
        • Martin WJ
        • Gupta NK
        • Loo CM
        • et al.
        Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing.
        Pain. 1999; 80: 57-65
        • Millan MJ
        Descending control of pain.
        Prog Neurobiol. 2002; 66: 355-474
        • Millan MJ
        • Lejeune F
        • Gobert A
        Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents.
        J Psychopharmacol. 2000; 14: 114-138
        • Morgan D
        • Cook CD
        • Smith MA
        • et al.
        An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity.
        Anesth Analg. 1999; 88: 407-413
        • Nicholas AP
        • Hokfelt T
        • Pieribone VA
        The distribution and significance of CNS adrenoceptors examined with in situ hybridization.
        Trends Pharmacol Sci. 1996; 17: 245-255
        • Nygren LG
        • Olson L
        A new major projection from locus coeruleus: the main source of noradrenergic nerve terminals in the ventral and dorsal columns of the spinal cord.
        Brain Res. 1977; 132: 85-93
        • Orr HE
        • Roughan JV
        • Flecknell PA
        Assessment of ketamine and medetomidine anaesthesia in the domestic rabbit.
        Vet Anaesth Analg. 2005; 32: 271-279
        • Sawamura S
        • Kingery WS
        • Davies MF
        • et al.
        Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors.
        J Neurosci. 2000; 20: 9242-9251
        • Sawynok J
        The 1988 Merck Frosst Award. The role of ascending and descending noradrenergic and serotonergic pathways in opioid and non-opioid antinociception as revealed by lesion studies.
        Can J Physiol Pharmacol. 1989; 67: 975-988
        • Sawynok J
        • Reid A
        Effect of 6-hydroxydopamine-induced lesions to ascending and descending noradrenergic pathways on morphine analgesia.
        Brain Res. 1987; 419: 156-165
        • Sharp J
        • Zammit T
        • Azar T
        • et al.
        Recovery of male rats from major abdominal surgery after treatment with various analgesics.
        Contemp Top Lab Anim Sci. 2003; 42: 22-27
        • Sullivan AF
        • Dashwood MR
        • Dickenson AH
        Alpha 2-adrenoceptor modulation of nociception in rat spinal cord: location, effects and interactions with morphine.
        Eur J Pharmacol. 1987; 138: 169-177
        • Sullivan AF
        • Kalso EA
        • McQuay HJ
        • et al.
        The antinociceptive actions of dexmedetomidine on dorsal horn neuronal responses in the anaesthetized rat.
        Eur J Pharmacol. 1992; 215: 127-133
        • Tomemori N
        • Komatsu T
        • Shingu K
        • et al.
        Activation of the supraspinal pain inhibition system by ketamine hydrochloride.
        Acta Anaesthesiol Scand. 1981; 25: 355-359
        • Vachon P
        • Moreau JP
        Butorphanol decreases edema following carrageenan-induced paw inflammation in rats.
        Contemp Top Lab Anim Sci. 2002; 41: 15-17
        • Verstegen J
        • Fargetton X
        • Donnay I
        • et al.
        An evaluation of medetomidine/ketamine and other drug combinations for anaesthesia in cats.
        Vet Rec. 1991; 128: 32-35
        • Verstegen J
        • Fargetton X
        • Zanker S
        • et al.
        Antagonistic activities of atipamezole, 4-aminopyridine and yohimbine against medetomidine/ketamine-induced anaesthesia in cats.
        Vet Rec. 1991; 128: 57-60
        • Yaksh TL
        Direct evidence that spinal serotonin and noradrenaline terminals mediate the spinal antinociceptive effects of morphine in the periaqueductal gray.
        Brain Res. 1979; 160: 180-185
        • Zhao ZQ
        • Gao YJ
        • Sun YG
        • et al.
        Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward.
        Proc Natl Acad Sci U S A. 2007; 104: 14519-14524