Elsevier

Brain Research

Volume 1070, Issue 1, 27 January 2006, Pages 35-44
Brain Research

Research Report
Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: Evidence for multiple diverse hyperalgesic systems

https://doi.org/10.1016/j.brainres.2005.11.054Get rights and content

Abstract

Hyperalgesia following chronic morphine treatment is thought to be a response to opioid receptor activation and analgesia and contribute to the development of analgesic tolerance. Here, the relationship between these variables was studied in mice tested for nociceptive sensitivity on the tail-withdrawal test during chronic infusion of various morphine doses. Hyperalgesic onset was preceded by dose-dependent analgesia except for the lowest morphine dose, which caused hyperalgesia 6 h after the start of infusion. Morphine ED50 values obtained at various infusion intervals demonstrated both analgesic tolerance in the absence of hyperalgesia and hyperalgesia in the absence of tolerance. Continuous opioid receptor antagonism using naltrexone pellets abolished analgesia during continuous morphine administration, transiently potentiated hyperalgesia, and revealed differences in hyperalgesic onset between morphine infusion doses. Acute injection of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 attenuated hyperalgesia in naltrexone-treated mice, demonstrating a role for this receptor in morphine hyperalgesia unrelated to its effects upon morphine analgesia. In mice where hyperalgesia subsided after continuous infusion of the highest morphine dose (i.e., hyperalgesic adaptation), hyperalgesia was restored after infusing the lower but not higher morphine dose. In addition, acute injection of morphine-3β-glucoronide (M3G) caused hyperalgesia that was cross-adaptive with the lower morphine dose only. The data demonstrate that morphine hyperalgesia is independent of prior or concurrent opioid receptor activity or analgesia and is unrelated to analgesic tolerance. Furthermore, the lack of hyperalgesic cross-adaptation between high and low morphine doses, and their differential cross-adaptation with M3G hyperalgesia, also suggests distinct morphine dose-dependent hyperalgesic systems.

Introduction

Opioids such as morphine remain the most efficacious and widely used analgesics for moderate to severe pain. Numerous clinical studies indicate that sustained opioid treatment can also paradoxically cause hyperalgesia, characterized by lowered nociceptive thresholds (De Conno et al., 1991, Sjogren et al., 1998). These findings are supported experimentally in rodent models where thermal hypersensitivity is observed consequent to morphine delivery via spinal (Mao et al., 1994, Woolf, 1981) and systemic (Li et al., 2001, Mao et al., 2002, Vanderah et al., 2001, Xie et al., 2005) routes of administration. Based on a variety of studies, opioid-induced hyperalgesia is currently conceptualized to be a physiological antagonist to analgesia, acting as a continuous foil to analgesia in an opioid-mediated opponent-process (Simonnet and Rivat, 2003), or recruited as a systems-level adaptive response elicited by prolonged opioid exposure (Ossipov et al., 2004). A receptor-mediated mechanism for hyperalgesia has also been proposed in which opioids sensitize spinal neurons, and thus increase pain sensitivity, by acting on subpopulations of opioid receptors coupled to excitatory cholera toxin-sensitive G-proteins (i.e., Gs) (see review Crain and Shen, 2000). While less abundant than pertussis-toxin-sensitive Gi/o-coupled opioid receptors that mediate analgesia, they are effective at remarkably low opioid agonist and antagonist concentrations so that their selective activation by very low systemic morphine doses (ca. 0.1 μg/kg) elicits acute thermal hyperalgesia, and their selective blockade using ultra-low doses (ca. 1–100 pg/kg) of naltrexone, a wide-spectrum opioid antagonist, unmasks potent morphine analgesia in mice (Crain and Shen, 2001). Importantly, hyperalgesia persists during uninterrupted opioid delivery (Vanderah et al., 2001, Xie et al., 2005) and is therefore not simply a consequence of “mini withdrawal” episodes unmasked when morphine occupation of opioid receptors is greatly reduced, such as might occur between long morphine inter-injection intervals, or following administration of an a opioid antagonist (Gutstein, 1996).

In addition to hyperalgesia, prior morphine exposure may cause a loss in analgesic potency, or tolerance, and results from various experimental approaches suggest that morphine hyperalgesia and tolerance are interrelated. For example, tolerance and opioid-induced hyperalgesia display overlapping neuroanatomical (Vanderah et al., 2001) and neurochemical (Mao et al., 2002, Shen and Crain, 2001, Vanderah et al., 2000, Xie et al., 2005) substrates and are both sensitive to various pharmacological interventions (Mao et al., 2002, Shen and Crain, 2001, Xie et al., 2005), including N-methyl-d-aspartate (NMDA) receptor blockade (Elliott et al., 1995, Li et al., 2001, Mao et al., 2002, Plesan et al., 1999). The magnitude of morphine analgesic tolerance and hyperalgesia in eleven inbred mouse strains also displays significant correlation, indicative of their genetic commonality (Kest et al., 2002). Morphine tolerance has long defied cogent mechanistic explanation, and these associations between hyperalgesia and tolerance have prompted many to identify hyperalgesia as a causative factor in morphine analgesic tolerance (Ossipov et al., 2004, Shen and Crain, 2001, Simonnet and Rivat, 2003, Xu et al., 2003). Accordingly, increasing morphine doses to maintain a desired analgesic response in tolerant subjects is required to offset increased nociceptive sensitivity in subjects rendered hyperalgesic by repeated morphine exposure.

In the present study, we tested several assumptions regarding the relationship between morphine analgesia, hyperalgesia, and tolerance in mice receiving continuous morphine infusion to minimize possible “mini withdrawal” episodes (Gutstein, 1996, Ossipov et al., 2004). For example, we tested whether hyperalgesia might be a causative factor in tolerance by comparing morphine analgesic potency at various stages of morphine infusion and hyperalgesia. Whether hyperalgesia is related to morphine analgesia was also considered by testing mice implanted with pellets of naltrexone (NTX), a broad-spectrum opioid receptor antagonist, prior to morphine infusion. Our finding that hyperalgesia was indeed unaffected by blockade of morphine analgesia then afforded the opportunity to determine whether the ability of NMDA receptor antagonists to attenuate morphine hyperalgesia reflects the direct participation of NMDA receptors in hyperalgesia or is simply the consequence of NMDA antagonists potentiating concurrent morphine analgesia (Kozela et al., 2001, Nemmani et al., 2004) obfuscated by hyperalgesia. Finally, since differences in hyperalgesic onset between high and low morphine infusion doses – particularly salient during NTX blockade of morphine analgesia – suggest that each may utilize somewhat distinct hyperalgesic mechanisms, we tested for hyperalgesic cross-adaptation between these morphine doses and similarly between these morphine doses and the pronociceptive metabolite morphine-3β-glucoronide (M3G) (Bartlett et al., 1994a, Bartlett et al., 1994b, Woolf, 1981, Yaksh et al., 1986).

Section snippets

Morphine hyperalgesia dose– and time–responses

To assess the hyperalgesic magnitude and duration of various morphine infusion doses, mice were implanted with pumps containing saline or 1.6, 8.0, and 40.0 mg/kg morphine. Latencies of saline-treated control mice did not vary from those obtained prior to the start of infusion (baseline (BL); Day 0) across 14 days of repeated daily testing (data not shown), demonstrating no effect of repeated measurement on nociception. Continuous infusion of both 8.0 and 40.0 mg/kg morphine resulted in an

Discussion

The major findings of the present study were as follows. NTX pellets providing continuous opioid receptor blockade during morphine infusion did not block hyperalgesia and diminished the ability of the NMDA receptor antagonist MK-801 to reverse hyperalgesia. Acute bolus morphine injections used to generate analgesia dose–response curves in mice undergoing morphine infusion revealed that tolerance was not temporally related to hyperalgesic onset, offset, or magnitude. In mice adapted to

Subjects

All procedures were approved by the College of Staten Island/City University of New York Institutional Animal Care and Use Committee and conform to guidelines of the International Association for the Study of Pain. Adult male CD-1 mice (Charles Rivers, Kingston, NY) were maintained on a 12:12-h light/dark cycle in a climate-controlled room with free access to food and tap water. Each subject was used once. For all conditions, n ≥ 7.

Nociceptive assay

The tail-withdrawal test of D'amour and Smith (1941) was chosen

Acknowledgments

Supported by CSI/IBR Center for Developmental Neuroscience (AJ, BK) and a grant from PSC/CUNY (BK). Thanks to Drs. C.E. Inturrisi, J.S. Mogil, and E. Balaban for their suggestions.

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