Surprising Separation of Cannabinoid Physical Dependence and Withdrawal in an Invertebrate Model

Wanhui Sheng,Robert B Raffa

doi:10.4236/pp.2018.912038

Abstract

Planarians have mammalian-like neurotransmitter systems and have been established as a novel in vivo model for neuropharmacology. In previous research, planarians that have been exposed to the cannabinoid receptor (CB-R) agonist WIN 55,212-2 for 1 h displayed abstinence-induced withdrawal when tested in drug-free, but not in drug-containing, water. The goals of the present study were to extend previous work and to further establish a cannabinoid behavioral model with planarians. The results showed 1) four different CB-R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly blocked development of physical dependence induced by two different CB-R agonists (WIN 55,212-2 and JWH251); 2) none of the same four antagonists (AM251, AM281, SLV319 or SR144528) precipitated withdrawal; 3) short wavelength (254 nm), but not long wavelength (366 nm), ultraviolet (UV) light attenuated abstinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal behavior. The results confirm the use of a planarian model as a simple yet robust way to study development of physical dependence to cannabinoid agonists. The effect of UV irradiation adds to the evidence that the results are receptor-related. The results also give rise to the surprising suggestion, within the limitations of the methodology, that development of cannabinoid physical dependence and antagonist-induced precipitated withdrawal might be separable phenomena in planarians.

Highlights

IntroductionPlanarians have neurotransmitter systems similar (or analogous) to higher organisms [1]
The results showed 1) four different CB-R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly blocked development of physical dependence induced by two different CB-R agonists (WIN 55,212-2 and JWH251); 2) none of the same four antagonists (AM251, AM281, SLV319 or SR144528) precipitated withdrawal; 3) short wavelength (254 nm), but not long wavelength (366 nm), ultraviolet (UV) light attenuated abstinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal behavior
All the antagonists (AM251, AM281, SLV319 and SR144528) showed certain ability to prevent the development of physical dependence induced by two agonists (WIN 55,212-2 and JWH251), expressed as the increased planarians by using the spontaneous locomotor velocity (pLMV) of planarians pretreated in combinations of agonists and antagonists placed in drug-free water compared with planarians pretreated with agonists alone tested in water (Figure 2)

Summary

Introduction

Planarians have neurotransmitter systems similar (or analogous) to higher organisms [1]. Planarians are established as an invertebrate model in regeneration, pharmacologists have used the model to study behavioral changes elicited by abused compounds [2] [3] [4] [5] [6]. Raffa and colleagues developed a quantitative method for measuring planarian locomotor activity [7] and applying the metric to phenomena related to drug use/abuse such as the development of physical dependence and withdrawal [8] [9] [10]. Planarian pharmacological behavior model is robust and sensitive, and offers unique advantages compared to rodents

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