The inhibitory effects of local anaesthetics on the vascular flare responses to bradykinin and substance P in human skin*

Abstract

SummaryBradykinin and substance P are involved in inflammation and act through Gq-protein-coupled receptors. Local anaesthetics inhibit the signalling of these receptors and have potent antiinflammatory actions. The aim of this study was to investigate the effects of local anaesthetics on the cutaneous flare responses to bradykinin and substance P. Skin blood flow responses to intradermal injections of bradykinin and substance P were assessed in the absence and presence of anaesthetic and analgesic concentrations of lidocaine, levobupivacaine and ropivacaine. All local anaesthetics significantly attenuated the vascular responses to bradykinin (p = 0.001) and substance P (p < 0.001). There were no differences in this effect between the different agents, but anaesthetic concentrations had a greater attenuating effect than analgesic concentrations on the substance P response (p < 0.001). Local anaesthetics may therefore be useful in the suppression of inflammation and the prevention of postoperative hyperalgesia. Bradykinin and substance P are chemical mediators involved in the inflammatory response, which act predominantly through the Gq-protein-coupled B2 and NK1 receptors, respectively [12,13]. Their intradermal administration elicits pain and a cutaneous flare and wheal response, reflecting vasodilation and increased vascular permeability [14]. As local anaesthetics are known to inhibit Gq protein function, and have been shown to affect B2 and NK1 receptor signalling in vitro [15,16], we hypothesised that they would attenuate the flare responses to exogenous bradykinin and substance P in human skin.The aim of this study was to investigate the effects of lidocaine, levobupivacaine and ropivacaine on the flare responses to bradykinin and substance P in the peripheral skin of healthy humans.

Multiple Inhibitory Mechanisms of Lidocaine on Bradykinin Receptor Activity in Model Sensory Neurons

“…In support of this conjecture, the vascular flare response to both BK and SP is inhibited by LID, suggesting that there are direct effects in vivo on these receptors or on their downstream pathways. 18 Surprisingly, we found no inhibition of BK responses by bupivacaine, although that LA was effective, and LID was not, in reducing the calcium response of these same cell types to endothelin 1, via ETA receptors, also GPCRs using the G q/11 alpha subunit for signaling. 5 We surmise that the docking position for G proteins, a probable locus for LA actions, 3 differs between these receptors, and that accounts for their differential sensitivity to LAs.…”

Effects of Lidocaine, Bupivacaine, and Ropivacaine on Calcitonin Gene-Related Peptide and Substance P Levels in the Incised Rat Skin

“…The vasoconstrictive effect of ropivacaine, 43 which contrasts to the vasodilator effect of lidocaine, may affect the vascular response, leading to inaccuracies in estimating the action of SP. 2 However, this hypothesis needs to be tested in further studies. The effects of levobupivacaine cannot be compared with those of bupivacaine because there are differences between their chemical structures.…”

“…All local anesthetics significantly attenuated the vascular responses to bradykinin and SP with no significant differences among agents, but higher concentrations had a greater attenuating effect than lower concentrations on the SP response. 2 This indirect assessment of the effects of local anesthetics on cutaneous flare responses to SP may be subjected to bias because, besides SP, the local anesthetics also act as vasodilators. The vasoconstrictive effect of ropivacaine, 43 which contrasts to the vasodilator effect of lidocaine, may affect the vascular response, leading to inaccuracies in estimating the action of SP.…”

“…1 Other effects associated with local anesthetics, including anti-inflammatory, antithrombotic, and neuroprotective actions, cannot be explained solely by the blockage of sodium channels. 2 The nervous system is present in the skin, especially in the dermis, as a complex 3-dimensional network that modulates immune and inflammatory responses, controls thermoregulation and homeostasis, and is involved in wound healing and regulation of skin appendages. 3Y6 Neurogenic inflammation refers to the initial stage of the peripheral inflammatory process caused by exogenous stimuli (eg, heat, topical lesions, irritating agents, allergens, ultraviolet light, and microbial agents) or endogenous stimuli (eg, pH changes, cytokines, kinins, histamine, proteases, neurotransmitters, hormones, and stress), which are conducted to the spinal cord in dromic d\irection.…”

Systemic Ropivacaine Diminishes Pain Sensitization Processes: A Randomized, Double-Blinded, Placebo-Controlled, Crossover Study in Healthy Volunteers

“…Recently published data on the effect of low-dose ropivacaine on mechanisms of peripheral neurogenic inflammation concluded that ropivacaine may be useful in the suppression of inflammation, mechanical and visceral hypersensitivity [14, 15]. Some authors even consider ropivacaine to be a promising alternative to systemic lidocaine which is used to treat chronic pain states [16].…”