<b>Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in </b><b>mice </b>

Abstract

This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalininduced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO-and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.The essential oil of bergamot (BEO; Citrus bergamia Risso) is one of the most commonly used essential oils and is familiar to most of the general public. BEO is obtained by cold pressing of the epicarp and part of the mesocarp of the fresh bergamot fruit. BEO consists of a volatile (93-96%) and a nonvolatile fraction (4-7%); the former contains monoterpene and sesquiterpene hydrocarbons and oxygenated derivatives such as linalool and linalyl acetate, while the latter fraction contains waxes, polymethoxylated flavones, coumarins, and psoralens such as bergamottin and bergapten (6,14). BEO has been reported to minimize symptoms of stress-induced anxiety and mild mood disorders, as well as cancer pain, however the mechanistic basis for its use in such applications awaits discovery (1). A previous in vitro study showed that BEO reduced neuronal damage caused by excitotoxic stimuli (5), and significantly increased the extracellular levels of the inhibitory amino acid neurotransmitter gamma-aminobutyric acid (GABA) in rat hippocampus (15). Linalool is a monoterpene compound and is the main volatile component of the essential oils of various plants, including BEO. It has previously been reported that linalool administration produced antibacterial, anticonvulsant, and anti-inflammatory effects, as well as showing antinociceptive activity in several behavioral assays (2)(3)(4)(16)(17)(18)(19)(20). Furthermore, linalool can significantly reduce both mor-

Aromatherapy and Aromatic Plants for the Treatment of Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: Clinical Evidence and Possible Mechanisms

“…Another fundamental facet is the increase of pain states in demented patients that are particularly related to agitation and aggression [16]. There is promising evidence for the effectiveness of aromatherapy for managing chronic pain: it was demonstrated that the intraplantar administration of Bergamot Essential Oil (BEO), a citrus fruit belonging to the Rutaceae family, significantly attenuates capsaicin-induced nociceptive behaviour [63] and both the first and the second phase of formalin-induced nocifensive response, thus confirming the previous observation that BEO reduces mechanical allodynia in neuropathic pain models [64–66]. Therefore, more rigorous RCTs assessing the effectiveness of aromatherapy on BPSDs, with recruitment of larger samples of patients and longer duration, are needed [21].…”

Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats

“…Untreated pain is a major contributor to reduced quality of life and disability in dementia patients, and can lead to increased behavioural and psychological symptoms of dementia (BPSD) [ 59 , 60 ]. Therefore, the behavioural effects reported herein in conjunction with its established analgesic properties [ 13 , 14 , 15 , 16 , 17 , 18 ] could provide the rational basis to the use of BEO at reducing BPSD associated with dementia.…”

“…BEO is used to facilitate wound healing as antiseptic and antihelminthic, effects that are supported by antimicrobial [ 5 ] and antifungal [ 6 ] activities as well as the capacity of the phytocomplex to increase oxidative metabolism in human polymorphonuclear leukocytes [ 7 ]. Furthermore, data accumulated in the literature so far indicate that bergamot oil is endowed with notable neurobiolological effects (see [ 8 , 9 ]) originating, at least in part, by an interference with basic mechanisms finely tuning synaptic plasticity under physiological [ 10 , 11 ] as well as pathological conditions, i.e., brain ischemia [ 12 ] and pain [ 13 , 14 , 15 , 16 , 17 , 18 ], induced under controlled and broadly validated experimental settings. Interestingly, BEO also showed neuroprotective effects in human neuroblastoma cell line [ 19 , 20 , 21 , 22 ].…”

Neuropharmacology of the neuropsychiatric symptoms of dementia: possible targets for novel therapeutic approaches

“…Therefore, aromatherapy using an essential oil endowed with strong analgesic properties could be even more useful in the management of BPSDs as agitation [69]. BEO has been proven to exert analgesic activity both in inflammatory [70][71][72] and in neuropathic [73,74] pain models, also via inhalatory route of administration [75]. The analgesic properties of BEO are reported in Table 1.…”

“…Plantar subcutaneous [72]. BEO (10 µg) significantly inhibited the nociceptive response to 2% formalin, only in the ipsilateral side, and this effect was antagonized by naloxone hydrochloride and methiodide [72]. Katsuyama et al, 2015 [72].…”