Effect of prior treatment with ultra-low-dose morphine on opioid- and nerve injury-induced hyperalgesia in rats


  • Elzbieta P. Wala, PhD
  • Paul A. Sloan, MD
  • Joseph R. Holtman Jr, MD, PhD




opioid-induced hyperalgesia, subanalgesic dose opioid, pre-emptive treatment, neuropathic pain prevention and reversal


Background: In addition to producing analgesia, opioids can increase sensitivity to pain (opioid-induced hyperalgesia [OIH]) in humans and rodents. Tolerance/OIH is likely mediated by similar mechanisms that lead to development of hyperalgesia after nerve injury (neuropathic pain). OIH may be a reason for loss of opioid efficacy and/or a worsening of pain. Ultra-low-dose (ULD) opioid evokes hyperalgesia independently of analgesia. Tolerance to ULD-OIH develops with repeated dosing in rats.
Objective: The effects of ULD opioids were characterized in two distinct situations where hyperalgesia is expected to occur: following acute opioid treatment and after nerve injury.
Design: First, ULD morphine was repeatedly administered (2× day for 5 days) by intrathecal (i.t., 0.01 μg) or intraperitoneal (i.p., 20 μg/kg) routes in rats. Second, morphine (0.01 μg i.t.; 20 μg/kg i.p.) was administered (2× day for 5 days) prior to acute morphine (30 μg i.t.; 10 mg/kg i.p). Third, ULD morphine (20 μg/kg/2× day, i.p.) was given either immediately after nerve injury (days 1-28) or when hyperalgesia was manifested (days 7-14). The tail-flick and paw-pressure tests were used in noninjured and nerve-injured rats, respectively.
Results: Tolerance was developed to OIH with repeated ULD morphine by the i.p. route but not the i.t. route. Prior exposure to ULD morphine (i.p.) caused prolongation of morphine analgesia in intact rats and inhibition of the development (but not reversal) of hyperalgesia in nerve-injured rats. Abolishment of OIH (pain desensitization) may diminish activation of pain facilitatory systems due to nerve injury and opioid treatment.
Conclusions: Although the translational aspect of this preclinical study has limitations, the present data may suggest a new strategy for the pre-emptive use of ULD opioids to prevent the development of neuropathic pain with certain procedures or disease states.

Author Biographies

Elzbieta P. Wala, PhD

Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, Kentucky.

Paul A. Sloan, MD

Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, Kentucky.

Joseph R. Holtman Jr, MD, PhD

Department of Anesthesiology and Molecular Biology and Therapeutics, Loyola University Medical Center, Maywood, Illinois.


Angst MS, Clark JD: Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology. 2006; 104: 570-587.

Chu LF, Angst MS, Clark D: Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clin J Pain. 2008; 24: 479-496.

Mao J: Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain. 2002; 100: 213-217.

Ruscheweyh R, Sandkuhler J: Opioids and central sensitization: Induction and reversal of hyperalgesia. Eur J Pharmacol. 2005; 9: 149-152.

Simonnet G, Rivat C: Opioid-induced hyperalgesia: Abnormal or normal pain? Neuroreport. 2003; 14: 1-7.

Sandkuhler J, Benrath J, Brechtel C, et al.: Synaptic mechanism of hyperalgesia. In: Sandkuhler J, Bromm B, Gebhard GA (eds.): Progress in Brain Research. Vol. 129. Amsterdam, NL: Elsevier Science B.V., 2000: 81-100.

Angst MS, Koppert W, Pahl I, et al.: Short-term infusion of the μ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003; 106: 49-57.

Luginbuhl M, Gerber A, Schnider TW, et al.: Modulation of remifentanil analgesia, hyperalgesia, and tolerance by smalldose ketamine in humans. Anesth Analg. 2003; 96: 726-732.

Guignard B, Bossar AE, Crosle C, et al.: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000; 93: 409-417.

Chu LF, Clark DJ, Angst MS: Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study. J Pain. 2006; 7: 43-48.

Ram KC, Eisenberg E, Haddad M, et al.: Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain—New perspective of opioid-induced hyperalgesia. Pain. 2008; 139: 431-438.

Pud D, Cohen D, Lawenthal E, et al.: Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend. 2006; 82: 218-223.

Celerier E, Laulin JP, Corecuff JB, et al.: Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci. 2001; 21: 4074-4080.

Celerier E, Rivat C, Jun Y, et al.: Long-lasting hyperalgesia induced by fentanyl in rats. Anesthesiology. 2000; 92: 465-472.

Laulin JP, Larcher A, Celerier E, et al.: Long lasting increased pain sensitivity in rat following exposure to heroin for the first time. Eur J Neurosci. 1998; 10: 782-785.

Van Elstreate AC, Sitbon P, Trabold F, et al.: A single dose of intrathecal morphine in rat induces long-lasting hyperalgesia: The protective effect of prior administration of ketamine. Anesth Analg. 2005; 101: 1750-1756.

Vanderah TW, Ossipow MH, Lai J, et al.: Mechanism of opioid-induced pain and antinociceptive tolerance: Descending facilitation and spinal dynorphin. Pain. 2001; 92: 5-9.

Zimmermann M: Pathobiology of neuropathic pain. Eur J Pharmacol. 2001; 429: 23-37.

Crain SM, Shen KF: Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-lowdose naltrexone, unmasking potent opioid analgesia. Brain Res. 2001; 888: 75-82.

Esmaeilli-Machani S, Shimokawa N, Javan M: Low-dose morphine induced hyperalgesia through activation of Gas protein kinase C and L-type Ca2+ channels in rats. J Neurosci Res. 2008; 86: 471-479.

Galeotti N, Stefano GB, Guarna M, et al.: Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain. 2006; 123: 294-305.

Holtman JR Jr, Wala EP: Characterization of morphineinduced hyperalgesia in male and female rats. Pain. 2005: 114: 62-70.

Juni A, Klein G, Kest B: Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: Evidence for multiple diverse hyperalgesic systems. Brain Res. 2006; 1070: 35-44.

McNaull B, Trang T, Sutak M, et al.: Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists. Eur J Pharmacol. 2007; 560: 132-141.

Juni A, Klein G, Kowalczyk B, et al.: Sex differences in hyperalgesia during morphine infusion: Effect of gonadectomy and estrogen treatment. Neuropharmacology. 2008; 54: 1264-1270.

Yaksh TL, Rudy TA: Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976; 17: 1031-1036.

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

Hamman SR, Martin WR: Thermal evoked tail avoidance reflex; input-output relationship and their modulation. Brain Res Bull. 1992; 29: 507-509.

Randall LO, Selitto JJ: A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther. 1957; 111: 409-419.

Mao J, Price DD, Mayer DJ: Thermal hyperalgesia in association with the development of morphine tolerance in rats: Role of excitatory amino acid receptors and protein kinase C. J Neurosci. 1994; 14: 2301-2312.

Mao J: Overview on opioid-induced hyperalgesia. In Mao (ed.): Opioid-Induced Hyperalgesia. London, UK: Informa Healthcare, 2009: 1-8.

Crain SM, Shen KF: Antagonism of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Brain Res. 2000; 84: 121-131.

Mao J: Mechanism of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain. 1995; 62: 259-274.

Ossipov M, Lai J, King T, et al.: Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers. 2005; 80: 319-324.

Xu XJ, Colpeart F, Wiesenfeld-Hallin Z: Opioid hyperalgesia and tolerance versus 5-HT 1A receptor-mediated inverse tolerance. Trends Pharmacol Sci. 2003; 24: 634-639.

Holtman JR Jr, Wala EP: Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav. 2006; 83: 100-108.

Wala EP, Holtman JR Jr: Buprenorphine-induced hyperalgesia in the rat. Eur J Pharmacol. 2011; 651: 89-95.

Juni A, Klein G, Pintar JE, et al.: Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neuroscience. 2007; 147: 439-444.

Van Dorp EL, Kest B, Kowalczyk WJ, et al.: Morphine-6β-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009; 110: 1356-1363.

Waxman AR, Arout C, Caldwell M, et al.: Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Neurosci Lett. 2009; 462: 68-72.

Simonnet G: Opioids: From analgesia to anti-hyperalgesia. Pain. 2005; 118: 8-9.

Ueda H: Molecular mechanisms of neuropathic pain phenotypic switch and initiation mechanisms. Pharmacol Ther. 2006; 109: 57-77.

Mao J: NMDA and opioid receptors: Their interactions in antinociception, tolerance and neuroplasticity. Brain Res Rev. 1999; 30: 289-304.

Mao J: Opioid-induced abnormal pain sensitivity. Curr Pain Headache Rep. 2006; 10: 67-70.

Ossipow MH, Lai J, Malan TP Jr, et al.: Tonic descending facilitation as a mechanism of neuropathic pain. In Hansonn PT, Fields HL, Hill RG, Marchettini P (eds.): Neuropathic Pain: Pathophysiology and Treatment. Seattle, WA: International Association for the Study Pain, 2001: 107-124.

Porreca F, Ossipow MH, Gebhart GF: Chronic pain and medullary descending facilitation. Trends Neurosci. 2002; 25: 319-325.

Ballantyne JC: Opioids for chronic nonterminal pain. South Med J. 2006; 99: 1245-1255.

Eisenberg E, McNicol E, Carr DR: Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. JAMA. 2005; 393: 3043-3052.

Martin TJ, Eisenach JC: Pharmacology of opioid and nonopioid analgesics in chronic pain states. J Pharmacol Exp Ther. 2001; 299: 811-817.

Przewlocki R, Przewlocka B: Opioids in chronic pain. Eur J Pharmacol. 2001; 429: 79-91.

Rosenblum A, Marsch LA, Herman J, et al.: Opioids and the treatment of chronic pain: Controversies, current status, and future decisions. Exp Clin Psychopharmacol. 2008; 16: 405-416.

Christensen D, Kayser V: The development of pain-related behavior and opioid tolerance after neuropathy-inducing surgery and sham surgery. Pain. 2000; 88: 231-238.

Neil A, Kayser V, Chen YL, et al.: Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy. Brain Res. 1990; 522: 140-143.

Benrath J, Brechtel C, Eike M, et al.: Low doses of fentanyl block central sensitization in the rat spinal cord. Anesthesiology. 2004; 100: 1545-1551.

Liu T, van Rooijen N, Tracey DJ: Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury. Pain. 2000; 86: 25-32.

Burges SE, Gardell LR, Ossipov MH, et al.: Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci. 2002; 22: 5129-5136.

Gardell LR, Vanderah TW, Gardell SE, et al.: Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J Neurosci. 2003; 23: 8370-8379.

Wang Z, Gardell LR, Ossipov MH, et al.: Pronociceptive actions of dynorphin maintain chronic neuropathic pain. J Neurosci. 2001; 21: 1779-1786.

Mao J, Price DD, Hayes RL, et al.: Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res. 1992; 598: 271-278.

Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther. 2003; 306: 624-630.

Vallejo R, Tilley DM, Vogel L, et al.: The role of glia and the immune system in the development and maintenance of neuropathic pain. Pain Pract. 2010; 10: 167-184.

Levy MH, Chwistek M, Mehta RS: Management of chronic pain in cancer survivors. Cancer J. 2008; 14(6): 401-409.

Sloan PA, Basta M, Storey P, et al.: Mexiletine as an adjuvant analgesic for the management of neuropathic pain. Anesth Analg. 1999; 89: 760-761.

Lema MJ, Foley KM, Hausheer FH: Types and epidemiology of cancer-related neuropathic pain: The intersection of cancer pain and neuropathic pain. Oncologist. 2010; 15 (Suppl 2): 3-8.

Kaley TJ, DeAngelis LM: Therapy of chemotherapy-induced peripheral neuropathy. Br J Haematol. 2009; 145: 3-14.

Kautio AL, Haanpaa M, Leminen A, et al.: Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms. Anticancer Res. 2009; 29: 2601-2606.



How to Cite

Wala, PhD, E. P., P. A. Sloan, MD, and J. R. Holtman Jr, MD, PhD. “Effect of Prior Treatment With Ultra-Low-Dose Morphine on Opioid- and Nerve Injury-Induced Hyperalgesia in Rats”. Journal of Opioid Management, vol. 7, no. 5, Sept. 2011, pp. 377-89, doi:10.5055/jom.2010.0079.