TRPV1 Antagonist Attenuates Postoperative Hypersensitivity by Central and Peripheral Mechanisms

Abstract

BackgroundAcute postoperative pain is one of the frequent reasons for pain treatment. However, the exact mechanisms of its development are still not completely clear. Transient receptor potential vanilloid 1 (TRPV1) receptors are involved in nociceptive signaling in various hypersensitive states. Here we have investigated the contribution of TRPV1 receptors expressed on cutaneous peripheral nociceptive fibers and in the spinal cord on the development and maintenance of hypersensitivity to thermal and mechanical stimuli following surgical incision. A rat plantar incision model was used to test paw withdrawal responses to thermal and mechanical stimuli. The effect of the TRPV1 receptor antagonist SB366791 was investigated 1) by intrathecal injection 15 min before incision and 2) intradermal injection before (30 min) and immediately after the surgery. Vehicle-injected rats and naïve animals treated identically were used as controls.ResultsPlantar incision induced mechanical allodynia and hyperalgesia and thermal hyperalgesia. A single intrathecal administration of SB366791 significantly reduced postincisional thermal hyperalgesia and also attenuated mechanical allodynia, while mechanical hyperalgesia remained unaffected. Local intradermal SB366791 treatment reduced thermal hyperalgesia and mechanical allodynia without affecting mechanical hyperalgesia.ConclusionsOur experiments suggest that both peripheral and spinal cord TRPV1 receptors are involved in increased cutaneous sensitivity following surgical incision. The analgesic effect of the TRPV1 receptor antagonist was especially evident in the reduction of thermal hyperalgesia. The activation of TRPV1 receptors represents an important mechanism in the development of postoperative hypersensitivity.

Engagement of signaling pathways of protease-activated receptor 2 and μ-opioid receptor in bone cancer pain and morphine tolerance

“…We also examined the role played by TRPV1 in mediating spinal PAR2 function. Figure a shows that intrathecal injection TRPV1 antagonist, SB366791 (100 μM), significantly attenuated mechanical and thermal hyperalgesia in bone cancer rats ( p < 0.05 vs . vehicle control, n = 12) as compared to vehicle injection ( n = 12).…”

Opioids and TRPV1 in the peripheral control of neuropathic pain – Defining a target site in the injured nerve

“…SB366791 has been characterized as an antagonist of human and rat TRPV1 activated by capsaicin, acid or noxious heat (50°C) in electrophysiological experiments in transfected cells, and its TRPV1 selectivity was verified in a wide range in vitro radioligand binding assays (testing 47 molecules, including G-protein-coupled receptors and ion channels) and in ex vivo rat brain slices using electrophysiological assays, including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurons (Gunthorpe et al, 2004) as well as current density recordings in T lymphocytes of TRPV1 knockout mice (Bertin et al, 2014). SB366791 has also been previously tested in vivo showing antiiflammatory effects in colonic inflammation (Bertin et al, 2014) and analgesic actions in models of acute, inflammatory and postoperative pain (Kanai et al, 2007;Niiyama et al, 2009;Fernandes et al, 2011;Uchytilova et al, 2014). Thus, SB366791 appears as a useful tool to examine the TRPV1 function; nevertheless, more studies are needed to verify its TRPV1 selectivity in vivo.…”

“…Neither such comparisons nor peripheral TRPV1 antagonist-induced analgesia in general were so far addressed in neuropathic pain. Interestingly, however, in inflammatory and postoperative pain models, TRPV1 blockers applied into inflamed paws also moderately reduced heat and mechanical sensitivity (Honore et al, 2005;Kanai et al, 2007;Fischer et al, 2013;Uchytilova et al, 2014). Since nerve damage is accompanied by local (at the injured trunk) inflammation as well (Perkins and Tracey, 2000;Labuz et al, 2009;Austin and Moalem-Taylor, 2010;Machelska, 2011) these data speculatively imply that inflammation might be a factor affecting the actions of TRPV1 antagonists.…”

“…Electrophysiological studies have shown that TRPV1-expressing sensory neurons process mechanical stimuli (McGaraughty et al, 2008;Brenneis et al, 2013) and capsaicin can lower mechanical thresholds in vivo (Honore et al, 2005;Binshtok et al, 2007), while TRPV1 knockout mice exhibited higher mechanical thresholds in longer-lasting peripheral inflammation and nerve injury (Szabo et al, 2005;Kim et al, 2012). Although not all (Wu et al, 2008;Uchytilova et al, 2014), several other studies reported reduction of mechanical sensitivity by TRPV1…”

“…TRPV1 is predominantly expressed in peripheral nociceptive neurons and was originally proposed to primarily mediate inflammatory heat hyperalgesia (Caterina et al, 1997(Caterina et al, , 2000. Nevertheless, in pharmacological approaches, systemically or centrally applied TRPV1 antagonists also attenuated heat sensitivity in neuropathic and postoperative pain (Pomonis et al, 2003;Vilceanu et al, 2010;Uchytilova et al, 2014). Although mechanistically less clear, there is accumulating evidence on the role of TRPV1 in mechanotransmission.…”