Delta- and mu-opioid pathways are involved in the analgesic effect of Ocimum basilicum L in mice

Abstract

Ethnopharmacological relevance

Ocimum basilicum L. is a perennial herb that has been used in traditional Asian Indian medicine for thousands of years as a natural anti-inflammatory, antibiotic, diuretic, and analgesic.

Aim of the study

The present study was conducted to investigate the analgesic effects of basil essential oil (BEO) in inflammatory pain models and identify underlying mechanisms. We further investigated whether BEO affects physiological pain and motor coordination.

Materials and methods

The analgesic effects of BEO were assessed in various mouse experimental pain models using formalin, acetic acid, heat, and carrageenan as stimuli. BEO was administered by intraperitoneal injection or inhalation. The involvement of various pathways in the analgesic effect of BEO was assessed by pretreating mice with selective pharmacological inhibitors, administered intraperitoneally. Opioid pathways were tested using the κ-opioid antagonist 5′-guanidinonaltrindole (GNTI; 0.3 mg/kg), δ-opioid antagonist naltrindole (NTD; 5 mg/kg) and μ-opioid antagonist naloxone (NAL; 8 mg/kg); nitric oxide (NO) pathways were tested using the NO synthase inhibitor N-nitro l-arginine methyl ester (L-NAME; 37.5 mg/kg) and NO precursor L-arginine (L-Arg; 600 mg/kg); and K_ATP channel pathways were tested using the ATP-sensitive K⁺ channel blocker, glibenclamide-hippuric acid (GHA, 2 mg/kg). Potential effects of BEO on motor coordination were assessed using a rotarod test.

Results

BEO exerted analgesic effects in all pain models. Notably, pretreatment with naltrindole, naloxone, or L-arginine significantly reduced the analgesic effects of BEO in the formalin test. BEO increased mean withdrawal latencies in a thermal plantar test at a high dose, but not at lower doses. BEO had no effect on motor coordination.

Conclusions

Our findings indicate that the analgesic effects of BEO are primarily mediated by delta- and mu-opioid pathways and further suggest that BEO has potential for development as an analgesic agent for the relief of inflammatory pain.

Introduction

Pain, defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (1979), is a common health problem for many people. According to the International Association for the Study of Pain, 20% of adults worldwide suffer from pain and 10% are newly diagnosed with chronic pain each year (Goldberg and McGee, 2011). Pain does not only causes physical discomfort, but it is also a contributor to many other problems, including mental health issues and economic impacts related to medical expenses and reduced productivity. Therefore, controlling pain is an important task.

Numerous drugs are clinically prescribed for controlling pain. Unfortunately, most of these drugs have a wide range of side effects ranging from mild to deadly, including drug addiction and respiratory depression. Therefore, continuing efforts to develop new therapeutic agents with higher safety profiles are important from a clinical standpoint. In this context, among the more notable potential sources of such agents are essential oils extracted from plants. Although essential oils, which consist of a number of different chemical compounds, have been used to effectively treat many diseases for thousands of years, they are not readily incorporated into the concept and development process of synthetic medicines, which are designed to target a single mechanism of action. As a result, these natural products have been excluded from the “medicine” category. However, the field of synthetic medicine has increasingly come to recognize that a multi-target/multi-component approach is effective for treating chronic diseases with complex pathogenic mechanisms, such as cancer, immune diseases, mental diseases, circulatory diseases and diseases associated with aging, among others (Oh, 2011). Thus, although essential oils have not yet been proven scientifically, their long history of clinical efficacy suggests that that they are a potential starting point for the development of new painkillers.

Ocimum basilicum L. (basil) is an annual plant belonging to Lamiaceae family, which includes more than 150 species of various botanical varieties and forms of basil distributed around the world (Pushpangadan, 1995). In traditional Asian Indian medicine (Rakshit and Ramalingam, 2010), basil is used as a natural anti-inflammatory, antibiotic (Srivastava et al., 2014), diuretic and analgesic (Al Abbasy et al., 2015). Also, leaves and flowering parts of O. basilicum are used as antispasmodic, aromatic, carminative, digestive, galactogogue, stomachic, and tonic agents in traditional medicine (Adigüzel, 2005). Notably, essential oil, steam-distilled from basil leaves, stems and flowers, has beneficial properties like high levels of antioxidants (Chenni, 2016). The main components of basil essential oil (BEO) are linalool, methyl cinnamate, methyleugenol, squalene, 2-methyltriacontane, 9-methyldotriacontane, β-sitosterol (El-Ghffar, 2018) and eugenol (Akgül, 1989). Among these, linalool and eugenol are known analgesic (Peana, 2004) as well as anti-inflammatory properties (Daniel, 2009) (Peana, 2002). This suggests that BEO is biologically active and can be used effectively in the context of pain control.

The present study was designed to investigate the analgesic effect of BEO through various mouse experimental pain models using formalin, acetic acid, heat, and carrageenan as noxious stimuli. In addition, we examined the involvement of opioid, K_ATP channel and nitric oxide (NO) pathways in the analgesic effects of BEO. Our findings demonstrate that the BEO exerts analgesic effects in pain models that are associated with delta- and mu-opioid pathways. We further found that BEO does not affect physiological pain or motor coordination.