Elsevier

Psychiatry Research

Volume 47, Issue 3, June 1993, Pages 267-280
Psychiatry Research

Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: A pilot study

https://doi.org/10.1016/0165-1781(93)90084-TGet rights and content

Abstract

To evaluate the role of opioids in Tourette's syndrome (TS), we performed a dose-response study of the behavioral and neuroendocrine effects of the selective k agonist spiradoline mesylate (U-62066E) in five TS patients and five normal control subjects, aged 20 to 47. The intramuscularly administered does of spiradoline were 0.0, 0.8, 1.6, and 3.2μg/kg. Baseline and postdrug tic frequencies were determined from “blind” videotape tic counts and bedside clinician ratings. In comparison with placebo, the lowest dose of spiradoline was associated with significant decreases in cumulative postdrug counts of total tics and phonic tics, as well as in clinician ratings of postdrug motor tic frequencies. By contrast, there was a trend for tic frequencies to increase following the intermediate dose (1.6μg/kg) of spiradoline. As a group, the TS subjects also secreted significantly more growth hormone following the 1.6 μg/kg dose of spiradoline than did the normal control subjects. These preliminary findings provide additional evidence for the involvement of opioids in TS and suggest (1) that opioids may exert dual modulatory effects on the expression of tic symptoms and (2) that some TS patients may be characterized by increased sensitivity of K receptors regulating growth hormone secretion.

References (67)

  • J.F. Leckman et al.

    The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale of tic severity

    Journal of the American Academy of Child and Adolescent Psychiatry

    (1989)
  • S. Li et al.

    Regulation of the concentration of dynorphin A[1–8] in the striatonigral pathway by the dopaminergic system

    Brain Research

    (1986)
  • A. Mansour et al.

    Anatomy of CNS opioid receptors

    Trends in Neuroscience

    (1988)
  • R.R. Matsumoto et al.

    Dopamine-independent motor behavior following microinjection of rimorphin in the substantia nigra

    Brain Research

    (1988)
  • A. Pfeiffer et al.

    Opiate receptor binding sites in human brain

    Brain Research

    (1982)
  • R. Quirion et al.

    Possible interactions between dynorphin and dopaminergic systems in rat basal ganglia and substantia nigra

    Brain Research

    (1985)
  • B.R. Seizinger et al.

    Opioid peptides in Huntington's disease: Alterations in prodynorphin and proenkephalin systems

    Brain Research

    (1986)
  • K.F. Shen et al.

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

    Brain Research

    (1989)
  • H. Taquet et al.

    Dynorphin levels in parkinsonian patients: Leu-enkephalin production from iether proenkephalin A or prodynorphin in human brain

    Brain Research

    (1985)
  • J.M. Walker et al.

    Opposite effects of mu and k opiates on the firing rate of dopamine cells in the substantia nigra of the rat

    European Journal of Pharmacology

    (1987)
  • L.L. Werling et al.

    Opioid receptor regulation of the release of norepinephrine in brain

    Neuropharmacology

    (1987)
  • P. Adamson et al.

    Alpha2-adrenergic, kappa-opiate, and P1-purinergic autoreceptors have mutually antagonistic effects: A new regulatory mechanism?

    Journal of Neurochemistry

    (1989)
  • C. Allgaier et al.

    Presynaptic kappa-opioid receptors on noradrenergic nerve terminals couple to G proteins and interact with the alpha2-adrenoceptors

    Journal of Neurochemistry

    (1989)
  • American Psychiatric Association

    DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders

    (1987)
  • R.P. Barrett et al.

    Effects of naloxone and naltrexone on self-injury: A double-blind, placebo-controlled analysis

    American Journal of Mental Retardation

    (1989)
  • R. Bruun et al.

    Opiate therapy and self-harming behavior in Tourette's syndrome

    Movement Disorders

    (1991)
  • P.B. Chappell et al.

    Biochemical and genetic studies of Tourette's syndrome

  • P.B. Chappell et al.

    Neuroendocrine and behavioral effects of naloxone in Tourette's syndrome

  • C. Chavkin et al.

    Dynorphin is a specific endogenous ligand of the K opioid receptor

    Science

    (1982)
  • J.A. Clark et al.

    Kappa opiate receptor multiplicity: Evidence for two U50,488-sensitive kappa1 subtypes and a novel kappa3 subtypes

    Journal of Pharmacology and Experimental Therapeutics

    (1989)
  • D.J. Cohen et al.

    Chronic, multiple tics of Gilles de la Tourette's disease: CSF acid monoamine metabolites after probenecid administration

    Archives of General Psychiatry

    (1978)
  • A.I. Faden et al.

    Dynorphin-related peptides cause motor dysfunction in the rat through a non-opiate action

    British Journal of Pharmacology

    (1984)
  • P.M. Gilbeau et al.

    Dynorphin effects on plasma concentrations of anterior pituitary hormones in the nonhuman primate

    Journal of Pharmacology and Experimental Therapeutics

    (1986)
  • Cited by (44)

    • Nalmefene, a mu opioid receptor antagonist/kappa opioid receptor partial agonist, potentiates cocaine motivation but not intake with extended access self-administration in adult male mice

      2021, Neuropharmacology
      Citation Excerpt :

      The kappa opioid receptor (KOR) may be a viable target for CUD given the counter modulatory effect of KOR activation on dopamine release (Devine et al., 1993) and ability to block cocaine evoked dopamine overflow in the striatum (Zhang et al., 2004a, b). However, centrally acting KOR full agonists have been shown to have aversive effects in rodents and humans (Bart et al., 2005; Chappell et al., 1993; Pfeiffer et al., 1986). Therefore, a KOR partial agonist that is able to block cocaine reward without the aversive effects observed with full agonists may be a more viable pharmacotherapeutic for CUD (Kreek et al., 2002).

    • Tourette disorder and other tic disorders

      2019, Handbook of Clinical Neurology
      Citation Excerpt :

      Identifying the most troublesome, focal, and typically simple tics is important prior to the use of BoNT (Thenganatt and Jankovic, 2016). Multiple additional agents have been studied for possible efficacy in TS, including glutamatergic agents, d-serine, riluzole (Lemmon et al., 2015), and N-acetylcysteine (Bloch et al., 2016a), nicotinic agents nicotine (McConville et al., 1992; Silver et al., 2001b; Howson et al., 2004), mecamylamine (Silver et al., 2001a), metoclopraminde (Nicolson et al., 2005), ondansetron (Toren et al., 2005), lithium (Kerbeshian and Burd, 1988), dopamine agonists, such as pramipexole (Kurlan et al., 2012) and talipexole (Goetz et al., 1994), naloxone (van Wattum et al., 2000), buspirone (Dursun et al., 1995), SSRIs (Scahill et al., 1997), vigabatrin (Catalyst Pharmaceutical Partners Inc., 2015), omega-3 fatty acid (Gabbay et al., 2012), physostigmine (Stahl and Berger, 1980), and spiradoline mesylate (Chappell et al., 1993). Some of these are based on hypotheses of the mechanism of TS development and treatment, e.g., glutamatergic agents (Lemmon et al., 2015); some have been effective in related disorders, e.g., SSRIs (Scahill et al., 1997); and some have been tried for other reasons.

    • Tourette Syndrome and Tic Disorders

      2016, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      TS symptoms have been exacerbated upon removal of chronic opiate treatment (Lichter et al., 1988). The use of a specific kappa receptor agonist, spiradoline, improved tics at a low dose, but had a paradoxical worsening at higher dose (Chappell et al., 1993). Studies evaluating opiate antagonists have also produced some conflicting results.

    • Psychiatric neural networks and neuropharmacology: Selected advances and novel implications

      2014, Saudi Pharmaceutical Journal
      Citation Excerpt :

      Importantly, it is admitted that all addictive drugs promote DA function (Di Chiara and Imperato, 1988; Wise and Bozarth, 1987) and buprenorphine, which is an opioid with an ability to disrupt KOR function, has been described with antidepressant effects (Bodkin et al., 1995) which link more KOR function to depression, moreover, this concept has been further fueled by findings. Indeed, KOR agonists, like spiradoline and enadoline, were pointed as a possible medication for mood disorders and, while spiradoline can reduce tics frequency and provoke sedation in patients with Tourette’s Syndrome (Chappell et al., 1993), enadoline can produce sedation, depersonalization, visual distortions, confusion and paranoia (Walsh et al., 2001a,b). On the other hand salvinorin A was also described with antidepressant effects (Carlezon et al., 2009).

    • Use patterns and self-reported effects of Salvia divinorum: An internet-based survey

      2010, Drug and Alcohol Dependence
      Citation Excerpt :

      Given that we did not ask participants detailed questions about their experiences with other drugs or for specific comparisons between SD and other drugs, we are limited in our ability to characterize the subjective effects of SD. Nonetheless, the reported effects of SD in our sample are generally consistent with KOR agonists’ known clinical effects, such as sedation, difficulty concentrating (Ashton et al., 1989; Chappell et al., 1993; Kramer et al., 2000; Martin et al., 1965; Pfeiffer et al., 1986; Reece et al., 1994; Rimoy et al., 1994; Walsh et al., 2001), auditory and visual distortions, and feelings of depersonalization (Chappell et al., 1993). In addition to the hallucinogen-like effects, Gonzalez et al. (2006) noted that 44% of their 32 participants reported experiencing some degree of adverse symptoms immediately after the acute effects of SD.

    View all citing articles on Scopus

    A portion of this study was presented at the Annual Meeting of the American College of Neuropsychopharmacology, San Juan, PR, December 16, 1989.

    View full text