Hypersensitivity Induced by Intrathecal Bradykinin Administration Is Enhanced by N-oleoyldopamine (OLDA) and Prevented by TRPV1 Antagonist.

Eva Uchytilova,Diana Spicarova,Jiri Palecek

doi:10.3390/ijms22073712

Abstract

Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.

Highlights

Analgesic effect of transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists was studied extensively and therapeutic potential in pain relief was demonstrated mainly in chronic neuropathic conditions [1,2,3,4,5,6]
Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal Transient receptor potential vanilloid 1 (TRPV1) channels
The paw withdrawal latency (PWL) were not affected when selective TRPV1 antagonist SB366791 (0.58 μg) was administered intrathecally, 15 min before BK (21.2 μg) and OLDA (0.42 μg) co-treatment (n = 7, Figure 1D). These results showed that enhanced sensitivity to heat induced by co-application of BK and OLDA might be mediated by TRPV1 stimulation

Summary

Introduction

Analgesic effect of transient receptor potential vanilloid 1 (TRPV1) agonists and antagonists was studied extensively and therapeutic potential in pain relief was demonstrated mainly in chronic neuropathic conditions [1,2,3,4,5,6]. We demonstrated the sensitization of spinal TRPV1 to endogenous agonist N-oleoyldopamine (OLDA) through bradykinin (BK), tumor necrosis factor-alpha or peripheral inflammation [19,20]. Proinflammatory mediator bradykinin undergoes rapid degradation, the metabolite desArg BK acts preferentially on kinin B1 receptor (B1R), which is inducible during pathological conditions. Bradykinin preferentially activates B2R constitutively expressed in normal tissue [21]. It was suggested that constitutively expressed B2R underlie the acute effect of BK, and inducible B1R underlie the chronic effect [21,22]

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