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In vivo and in vitro attenuation of naloxone-precipitated experimental opioid withdrawal syndrome by insulin and selective KATP channel modulator

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Abstract

Rationale

Opiate exposure for longer duration develops state of dependence in humans and animals, which is revealed by signs and symptoms of withdrawal precipitated by opioid receptor antagonists. The sudden withdrawal of opioids produces a withdrawal syndrome in opioid-dependent subjects. Insulin and ATP-sensitive potassium (KATP) channel-mediated glucose homeostasis have been shown to modulate morphine withdrawal.

Objective

Present study has been structured to investigate the role of insulin and pharmacological modulator of KATP channel (gliclazide) in experimental morphine withdrawal syndrome, both invivo and invitro.

Methods

In this study, naloxone-precipitated morphine withdrawal syndrome in mice (invivo) as well as in rat ileum (invitro) were utilized to assess opioid withdrawal phenomenon. Morphine withdrawal syndromes like jumping and rearing frequency, forepaw licking, circling, fore paw tremor, wet dog shake, sneezing, overall morphine withdrawal severity (OMWS), serum glucose, brain malondialdehyde (MDA), glutathione (GSH), nitrite/nitrate, and calcium (Ca+2) were assessed.

Results

Naloxone has significantly increased morphine withdrawal syndrome, both invivo and invitro. Insulin and gliclazide have significantly attenuated, naloxone induced behavioral changes like jumping and rearing frequency, forepaw licking, wet dog shake, sneezing, straightening, circling, OMWS, and various biochemical impairments such as serum glucose, brain MDA, GSH, nitrite/nitrate, and Ca+2 in morphine-dependent animals (invivo). In vitro, insulin and gliclazide have significantly reduced naloxone-induced contraction in morphine-withdrawn rat ileum preparation.

Conclusions

Insulin and gliclazide (KATP channel blocker) have attenuated naloxone-precipitated morphine withdrawal syndrome, both invivo and invitro. Thus, insulin and KATP channel modulation may provide new avenues for research in morphine withdrawal.

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Acknowledgements

The authors are thankful to the Space Age Research and Technical Foundation Charitable Trust (SPRFCT), Bharat Institute of Technology, Meerut, India, for providing all the necessary facilities and funding to conduct this research work. We are also thankful to Dr. Nirmal Singh, Associate Professor, Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala, Punjab, India, for his valuable suggestions.

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  1. Neuropharmacology Laboratory, Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, 250103, Uttar Pradesh, India

    Prabhat Singh & Surbhi Gupta

  2. Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, 250103, Uttar Pradesh, India

    Bhupesh Sharma & B. M. Sharma

  3. CNS Pharmacology, Conscience Research, Pocket F-233, B, Dilshad Garden, Delhi, 110095, India

    Bhupesh Sharma

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  1. Prabhat Singh
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Singh, P., Sharma, B., Gupta, S. et al. In vivo and in vitro attenuation of naloxone-precipitated experimental opioid withdrawal syndrome by insulin and selective KATP channel modulator. Psychopharmacology 232, 465–475 (2015). https://doi.org/10.1007/s00213-014-3680-5

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