Title: Novel Analgesic Potential of ß2-Agonists for Neuropathic Pain via ß2-Agonist Action.

PURPOSE OF REVIEW: Multimodal therapies are often employed to treat chronic pain, and ß2-agonists are a potential drug class that shows promise. The primary aim of this paper is to discuss the role of ß2-agonists as an adjunctive therapy for chronic pain based on the current literature. RECENT FINDINGS: Recent studies in mouse models have shown that the ß2-adrenergic system plays an essential role in the analgesic properties of antidepressant drugs used to treat neuropathic pain and that the adrenergic relies on an intact endogenous opioid system to be effective. Studies also show that ß2-agonism alone is adequate to exert anti-allodynic effects in a mouse model. This paper summarized the basic physiology and pharmacology of the sympathetic nervous system and specifically the ß2-adrenergic system and summarized current literature in its involvement in the treatment of chronic neuropathic pain.

Targeted metabolomic approach for assessing human synthetic cannabinoid exposure and pharmacology.

Designer synthetic cannabinoids like JWH-018 and AM2201 have unique clinical toxicity. Cytochrome-P450-mediated metabolism of each leads to the generation of pharmacologically active (ω)- and (ω-1)-monohydroxyl metabolites that retain high affinity for cannabinoid type-1 receptors, exhibit Δ(9)-THC-like effects in rodents, and are conjugated with glucuronic acid prior to excretion in human urine. Previous studies have not measured the contribution of the specific (ω-1)-monohydroxyl enantiomers in human metabolism and toxicity. This study uses a chiral liquid chromatography-tandem mass spectroscopy approach (LC-MS/MS) to quantify each specific enantiomer and other nonchiral, human metabolites of JWH-018 and AM2201 in human urine. The accuracy (average % RE = 18.6) and reproducibility (average CV = 15.8%) of the method resulted in low-level quantification (average LLQ = 0.99 ng/mL) of each metabolite. Comparisons with a previously validated nonchiral method showed strong correlation between the two approaches (average r(2) = 0.89). Pilot data from human urine samples demonstrate enantiospecific excretion patterns. The (S)-isomer of the JWH-018-(ω-1)-monohydroxyl metabolite was predominantly excreted (>87%) in human urine as the glucuronic acid conjugate, whereas the relative abundance of the corresponding AM2201-(ω-1)-metabolite was low (<5%) and did not demonstrate enantiospecificity (approximate 50:50 ratio of each enantiomer). The new chiral method provides a comprehensive, targeted metabolomic approach for studying the human metabolism of JWH-018 and AM2201. Preliminary evaluations of specific enantiomeric contributions support the use of this approach in future studies designed to understand the pharmacokinetic properties of JWH-018 and/or AM2201.