Elsevier

Neuroscience

Volume 161, Issue 2, 30 June 2009, Pages 381-391
Neuroscience

Behavioural Neuroscience
Research Paper
Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents

https://doi.org/10.1016/j.neuroscience.2009.03.053Get rights and content

Abstract

In the present study, we asked whether multiple intrathecal injections of deltorphin II, a selective delta opioid receptor (DOPR) agonist, induced DOPR tolerance in three behavioral assays. Unilateral inflammation caused by complete Freund's adjuvant (CFA) injection into the rat or mouse hind paw (CFA model) induced thermal hyperalgesic response that was transiently and dose-dependently reduced by intrathecal administration of deltorphin II or morphine. In both rodent species, the effect of deltorphin II was not modified by a single prior administration of deltorphin II, suggesting an absence of acute tolerance in this paradigm. Repeated administration of intrathecal deltorphin II or s.c. SB-235863 (five consecutive injections over 60 h) also failed to impair the antihyperalgesic response to delta opioid receptor agonist, whereas repeated intrathecal or s.c. injections of morphine induced a significant decrease in the subsequent thermal antihyperalgesic response to morphine. In mice, deltorphin II also induced a rapid, transient motor incoordination/ataxia-like behavior as tested with the accelerating rotarod. In contrast to the antihyperalgesic responses, tolerance to the motoric effect of deltorphin II was evident in mice previously exposed to multiple intrathecal agonist injections, but not multiple saline administrations. Using the tail flick antinociceptive test, we found that DOPR-mediated analgesia was significantly reduced by repeated exposure to deltorphin II. Altogether, these observations suggest that repeated injections of DOPR agonists induce differential tolerance effects on antihyperalgesic, antinociceptive, and motor incoordination/ataxia-like behaviors related to DOPR activation by deltorphin II.

Section snippets

Studies in rats

Adult male Sprague–Dawley rats (200–225 g; Charles-River, St-Constant, QC, Canada) were maintained on a 12-h light/dark cycle (6:00–18:00 h). Laboratory chow and water were available ad libitum. Studies were conducted between 7:00 and 11:00 (light cycle). Experiments were approved by the animal care committee of the Université de Sherbrooke in compliance with the policies and directives of the Canadian Council on Animal Care and guidelines from the International Association for the Study of

Unilateral inflammation: visual confirmation

Injection of CFA into the plantar surface of the right hind paw rapidly induced edema and swelling that persisted over at least 3 days (72 h), after which both rats and mice avoided bearing their body weight on their inflamed hind paw.

Experiments performed in rats.

Antihyperalgesic potency of intrathecal deltorphin II and morphine

As shown in Fig. 1A, intrathecal injection of deltorphin II induced a time- and dose-dependent alleviation of CFA-induced ipsilateral thermal hyperalgesia. For all effective doses of deltorphin II, the effect was maximal at 15 min

Discussion

In the present study, we investigated the effects of multiple injections of DOPR-selective agonists (deltorphin II and SB-235863) using various treatment and assessment paradigms. In a model of CFA-induced inflammation, we found a lack of both acute and chronic tolerance to delta agonists' antihyperalgesic effect. By contrast, when DOPR-mediated motor incoordination/ataxia-like and antinociception (acute pain) behaviors were assessed, repeated injection of deltorphin II was found to reduce

Conclusion

In conclusion, the present study proves the existence of a dichotomy between development of tolerance regarding diverse behavioral effects mediated by DOPR activation. In particular, we demonstrated a lack of antihyperalgesic tolerance to delta-selective agonists in a model of peripheral inflammation induced by injection of CFA into the plantar surface of the paw. As opposed to its antihyperalgesic effect, development of tolerance to deltorphin II was observed when its antinociceptive

Acknowledgments

We thank Nicolas Beaudet for his critical reading of the manuscript. This work was supported by grants MOP-84538 from the Canadian Institutes of Health Research (CIHR) to L.G. and DA11672 from the National Institutes of Health (NIH) to C.C. H.B. was the recipient of a scholarship from the Alexander Graham Bell Canada Graduate Scholarships Program awarded by the Natural Sciences and Engineering Research Council of Canada (NSERC).

References (66)

  • G.L. Fraser et al.

    The effects of delta agonists on locomotor activity in habituated and non-habituated rats

    Life Sci

    (2000)
  • L. Gendron et al.

    Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

    Neuroscience

    (2007)
  • L. Gendron et al.

    Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia

    Neuroscience

    (2007)
  • L. Hernandez et al.

    Tolerance to the antinociceptive effects of peripherally administered opioids expression of beta-arrestins

    Brain Res

    (2009)
  • S.V. Holdridge et al.

    Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

    Eur J Pain

    (2007)
  • P. Honore et al.

    Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons

    Neuroscience

    (2000)
  • Y. Hosohata et al.

    Delta-opioid receptor agonists produce antinociception and [35S]GTPgammaS binding in mu receptor knockout mice

    Eur J Pharmacol

    (2000)
  • J.L. Hylden et al.

    Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia: possible involvement of noradrenergic mechanisms

    Eur J Pharmacol

    (1991)
  • N. Kabli et al.

    Antiallodynic effects of peripheral delta opioid receptors in neuropathic pain

    Pain

    (2007)
  • E.S. Krames et al.

    Intrathecal d-ala2-d-leu5-enkephalin (DADL) restores analgesia in a patient analgetically tolerant to intrathecal morphine sulfate

    Pain

    (1986)
  • J.Y. Li et al.

    Morphine tolerance in arthritic rats and serotonergic system

    Life Sci

    (1999)
  • D.Y. Liang et al.

    Chronic pain and genetic background interact and influence opioid analgesia, tolerance, and physical dependence

    Pain

    (2006)
  • H. McQuay

    Opioids in pain management

    Lancet

    (1999)
  • J. Mika et al.

    The role of delta-opioid receptor subtypes in neuropathic pain

    Eur J Pharmacol

    (2001)
  • B.M. Onofrio et al.

    Intrathecal delta-receptor ligand produces analgesia in man

    Lancet

    (1983)
  • C. Qiu et al.

    Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor-deficient mice

    Eur J Pharmacol

    (2000)
  • A.F. Rahman et al.

    Involvement of pain associated anxiety in the development of morphine tolerance in formalin treated mice

    Jpn J Pharmacol

    (1994)
  • A. Saitoh et al.

    Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents

    J Pharmacol Sci

    (2004)
  • H.H. Szeto et al.

    Respiratory depression after intravenous administration of delta-selective opioid peptide analogs

    Peptides

    (1999)
  • L.F. Tseng et al.

    Antisense oligodeoxynucleotide to a delta-opioid receptor selectively blocks the spinal antinociception induced by delta-, but not mu- or kappa-opioid receptor agonists in the mouse

    Eur J Pharmacol

    (1994)
  • E.V. Varga et al.

    Agonist-specific regulation of the delta-opioid receptor

    Life Sci

    (2004)
  • G.M. Zhao et al.

    Effects of multiple intracerebroventricular injections of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II on tolerance to their analgesic action and on brain delta-opioid receptors

    Brain Res

    (1997)
  • E.J. Bilsky et al.

    SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist

    J Pharmacol Exp Ther

    (1995)
  • Cited by (42)

    • Metabolically stable neurotensin analogs exert potent and long-acting analgesia without hypothermia

      2021, Behavioural Brain Research
      Citation Excerpt :

      Behavioral experiments were performed by three female experimenters in a quiet room between 08.00 AM and 12.00 PM to reduce variation related to the circadian rhythm. Rats randomly assigned to control and experimental groups were lightly anesthetized with 2.5 % isoflurane/oxygen (Baxter corporation, Mississauga, ON, Canada; 2 L/min) and injected intrathecally (i.t.) with a 27 G1/2 needle in the L5 − L6 intervertebral space with 0.9 % saline or 25 μl of each compound, as previously published [44–46]. All NT(8−13) analogs were diluted in saline at 5 mg/mL.

    • Molecular aspects of delta opioid receptors

      2019, Vitamins and Hormones
      Citation Excerpt :

      In particular, ligands that induce transient association between DOP, βarr2 and Gβγ support recycling, and those that lock the receptor in a stable DOP-βarr2-Gβγ complex are excluded from this path (Audet et al., 2012). Among highly internalizing ligands, those that favor DOP recycling do not produce acute analgesic tolerance (Audet et al., 2012; Beaudry et al., 2009), while those that fail to support membrane recovery of the receptor induce rapid and sustained tolerance to their antinociceptive actions (Audet et al., 2012; Beaudry et al., 2009; Pradhan et al., 2009). Hence, internalization is informative as a predictor of tolerance, only if considered on relation to postendocytic routing of the internalized receptors.

    • Antinociceptive effect of d-Lys<sup>2</sup>, Dab<sup>4</sup> N-(ureidoethyl)amide, a new cyclic 1-4 dermorphin/deltorphin analog

      2014, Pharmacological Reports
      Citation Excerpt :

      Icv injections of some synthetic deltorphin analogs exerted catalepsy or a biphasic effect: low doses stimulated locomotion whereas higher doses initially suppressed, then increased locomotor activity [65]. Single intrathecal injection of deltorphin II in mice induced rapid and transient motor coordination disturbances as tested with the accelerating rota-rod [66]. In our study, iv administration of cUP-1 in the range of doses applied did not significantly influence locomotor activity of mice, when evaluated at the time of the peak antinociceptive activity, however we observed transient rigidity of the tail muscles especially after injection of the highest dose of cUP-1.

    View all citing articles on Scopus
    1

    Present address: AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA.

    View full text