TRPV1 antagonist, A‐889425, inhibits mechanotransmission in a subclass of rat primary afferent neurons following peripheral inflammation

Abstract

TRPV1 (transient receptor potential vanilloid family type 1) is a nonselective cation channel that is activated and/or sensitized by noxious heat, protons, and other endogenous molecules released following tissue injury. In addition, a role for TRPV1 in mechanotransmission is emerging. We have recently reported that a selective TRPV1 receptor antagonist, A-889425, reduces mechanical allodynia and spinal neuron responses to mechanical stimulation of complete Freund's adjuvant (CFA)-inflamed rat hind paws. The population of peripheral nerve fibers through which TRPV1 antagonists mediate their effect on mechanotransmission have not yet been described. The objective of this study was to characterize TRPV1-mediated modulation of mechanically evoked activity in sensory axons innervating rat hind paws. We used an in vitro skin-nerve preparation to record neural activity from single axons isolated from rat tibial nerve. Single fibers were classified by conduction velocity, mechanical threshold, and stimulus-response relationships. We used A-889425 to investigate uninjured and inflamed skin afferent neuron populations to evoked mechanical stimulation. Application of A-889425 had no effect on the mechanical responsiveness of Aδ and C-fiber units innervating uninjured skin. In contrast, A-889425 inhibited responses of slowly conducting Aδ fiber units to noxious mechanical stimulation in a population of axons innervating CFA-inflamed hind paws. These data support a role for TRPV1 in mechanotransmission following peripheral inflammation, and highlight the importance of a distinct subclass of primary afferent neurons in mediating this effect.

The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

“…administration in the CFAtreated, but not in the control rats. A higher susceptibility of inflamed afferents to pharmacological intervention has also been described before and allow suggestions that there is a change in the subpopulations of afferents involved in the transmission and/ or a change in the functional constitution with receptors involved in nociception (Brederson et al, 2012;Wenk et al, 2006). J-2156 had no effect on spontaneous activity in CFA-and control animals, suggesting that the main peripheral antinociceptive effect was achieved by the reduced mechanosensitivity to evoked stimuli.…”

“…The fact that we could not measure a significant increase in the firing rate of afferents after inflammation has been reported before in other studies using in-vitro skin nerve preparations (Brederson et al, 2012;Wenk et al, 2006). It is speculated that mechanically insensitive fibers are recruited and become mechanosensitive under inflammatory conditions.…”

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion

“…Current treatment of BTP commonly involves supplementation with rapidly absorbed opioids [15,47,66], and we show that Aδ responses are particularly sensitive to morphine. Additionally, the participation of TRPV1 + Aδ fibers suggests a vanilloid-based, non-opioid alternative for treatment of BTP [6]. …”

“…In the context of inflammatory processes, TRPV1-mediated hyperalgesia is associated with increased expression of the TRPV1 channel, alterations in its sensitivity by phosphorylation [5,53,56], and increased trafficking of the channel to the plasma membrane [75]. These cellular and molecular alterations underscore the complexities as well as the potentials for using TRPV1 antagonists [6,20,54,62], agonists [7,22,25,31], and positive allosteric modulators [32,39] in the therapeutic arena. However, among the AMH fibers, it has not yet been determined whether the capsaicin-sensitive TRPV1 + population is sensitized during inflammation, and the contribution of these fibers to hyperalgesia needs further investigation.…”

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

“…In our hands, a 5-min intertest interval is sufficient for full recovery of fiber response to mechanical stimulation. To inhibit TRPV1, we utilized A889425 (Abbott Laboratories, Abbott Park, IL), a highly selective competitive antagonist for the capsaicin-binding site with an IC 50 of ϳ300 nM (5,27). A889425 was dissolved in 1-methyl-2-pyrrolidinone (1M2P) and diluted to a final concentration in Krebs solution.…”