Regular Article
Sign-reversal during Persistent Activation in μ -Opioid Signal Transduction

https://doi.org/10.1006/jtbi.2001.2509Get rights and content

Abstract

A concept of signal transduction in biological systems specifies that any instantaneous input is appreciated by its departure from the moving average of past activity. The concept provides an adequate account of the occurrence of both the one-directional (e.g. analgesic) effects induced by opioid receptor activation, and of the contra-directional (e.g. hyperalgesic) effects that can be observed when activation is discontinued. Following this transduction concept, the numerical simulations reported here revealed, remarkably, that under some parametric conditions, the input's effect may reverse even as input is maintained at a constant magnitude. In in vitro conditions that are proximal to the signal transduction that occurs when an opioid agonist binds to the G-protein coupled opioid receptor, the effects of opioid receptor activation were monitored by measuring time-dependent Ca2+ responses in CHO-K1 cells transfected with a μ -opioid receptor and Gα 15 protein. The results indicate morphine to produce an initial increase in intracellular Ca2+ concentration followed by a decrease below basal level. The occurrence of a sign-reversal was confirmed in native conditions of receptor-to-G protein coupling; the continuous in vivo infusion over a 2-week period of 0.31 mg rat−1day−1 of fentanyl initially caused an increase of the mechanical threshold to induce a pain response (i.e. analgesia) that was followed by a decrease (i.e. hyperalgesia). The findings indicate that with opioid signaling systems, transduction mechanisms operate that may cause the sign of the effect to reverse not only when activation is discontinued but also whilst it is maintained at a constant magnitude.

References (57)

  • S.R. SAVAGE

    Addiction in the treatment of pain: significance, recognition, and management

    J. Pain Symptom Manage.

    (1993)
  • S.R. SAVAGE

    Long-term opioid therapy: assessment of consequences and risks

    J. Pain Symptom Manage.

    (1996)
  • J. SCHOFFERMAN

    Long-term use of opioid analgesics for the treatment of chronic pain of nonmalignant origin

    J. Pain Symptom Manage.

    (1993)
  • K.S. SCHROEDER et al.

    FLIPR: a new instrument for accurate, high throughput optical screening

    J. Biomol. Screen.

    (1996)
  • K.-F. SHEN et al.

    Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture

    Brain Res.

    (1989)
  • E. SUBLETTE et al.

    Stimulus frequency and intensity: critical determinants of opioid enhancement or inhibition of evoked methionine-enkephalin release

    Brain Res.

    (1992)
  • A.H. TANG et al.

    Comparison of subcutaneous and spinal subarachnoid injections of morphine and naloxone on analgesic tests in the rat

    Eur. J. Pharmacol.

    (1978)
  • C.B. TAYLOR et al.

    The effects of detoxification, relaxation, and brief supportive therapy on chronic pain

    Pain

    (1980)
  • C.J. WOOLF

    Intrathecal high dose morphine produces hyperalgesia in the rat

    Brain Res.

    (1981)
  • S.R. ZUKIN et al.

    Behavioral and biochemical stereoselectivity of sigma opiate/PCP receptors

    Brain Res.

    (1984)
  • R.A. BRODNER et al.

    Chronic pain exacerbated by long-term narcotic use in patients with nonmalignant disease: clinical syndrome and treatment

    Mt. Sinai J. Med.

    (1978)
  • L.A. BRUINS SLOT et al.

    A mechanism of signal transduction operating with opiate receptors

    Neurocomputing

    (2001)
  • BRUINS SLOT, L. A. TARAYRE, J.-P. KOEK, W. RIBET, J.-P. COLPAERT, F. C. Experimental conditions for the continuous...
  • S.N. CALDERON et al.

    Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(aR)-a((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N, N -diethylbenzamide (SNC80): a highly selective, nonpeptide delta opioid receptor agonist

    J. Med. Chem.

    (1994)
  • F.C. COLPAERT

    Narcotic cue, narcotic analgesia, and the tolerance problem: the regulation of sensitivity to drug cues and to pain by an internal cue processing model

  • F.C. COLPAERT

    System theory of pain and of opiate analgesia: no tolerance to opiates

    Pharmacol. Rev.

    (1996)
  • F.C. COLPAERT et al.

    Paradoxical signal transduction in neurobiological systems

    Mol. Neurobiol.

    (2001)
  • C.W. DUNNETT

    A multiple comparisons procedure for comparing several treatments with a control

    J. Am. Stat. Assoc.

    (1955)
  • Cited by (19)

    • Neurocircuitry basis of the opioid use disorder–post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework

      2022, The Lancet Psychiatry
      Citation Excerpt :

      Early work by Greenwald and colleagues clearly showed buprenorphine's pharmacological action directly at MOR1 in patients with OUD.99 The partial agonist mechanism of buprenorphine on MOR1 facilitates its ceiling effects on respiratory depression, sedation, and subjective measures of euphoria in conjunction with inverted U-shaped dose–response behaviour.97 Although the binding affinity of buprenorphine at KOR1, DOR1, and KOR3 is lower than at MOR1,100 the antagonistic effects of buprenorphine on KOR1 in particular might have further therapeutic implications.

    • Alcohol: Neurobiology of Addiction

      2021, Alcohol: Neurobiology of Addiction
    View all citing articles on Scopus
    1

    Author to whom correspondence should be addressed. E-mail: [email protected]

    View full text