Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation

Abstract

Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP) - induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions.

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

“…The presence of μ-opioid receptors on TRPV1 + DRG neurons [18] and colocalization of TRPV1 in subpopulations of Aδ neurons are consistent with the sensitivity of Aδ neurons to pharmacological doses of morphine [23]. These data suggest that μ-opioid-containing TRPV1 + Aδ neurons may contribute to a variety of chronic pain problems [6,15,23,31,49,55,79]. …”

“…The variation in TRPV1 levels seen in DRG neurons using immunocytochemistry (Fig. 6) [35,79] may contribute to the differential sensitivity of individual fibers to both heat and RTX-induced deactivation. Differential TRPV1 expression has important implications for the therapeutic use of TRPV1 agonists.…”

“…The range of TRPV1 expression [35,45,52,79] may be relevant to earlier neurophysiological classification of thermosensing Aδ fibers in primates [69]. High heat threshold type I fibers (>53 °C and capsaicin insensitive) may represent the very lowest-expressing TRPV1 + DRG neurons, whereas type II Aδ fibers (heat threshold −46 °C and capsaicin sensitive) express higher levels of TRPV1.…”

Effect of delayed intrathecal administration of capsaicin on neuropathic pain induced by chronic constriction injury of the sciatic nerve in rats

“…For instance, the TRPV1 antagonists provide a more profound attenuation of pain responses to noxious stimuli in rats with inflammatory pain, a state known to have increased TRPV1 activity 8. The state of TRPV1 also determines the analgesic efficacy of a combination of capsaicin and N-(2, 6-dimethylphenyl- carbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable sodium channel blocker 14. The QX-314 blocks nociceptive sodium channels from inside the cell, but it relies on coadministered capsaicin to bind the TRPV1 receptors and to allow entry via the transmembrane channels.…”

Prophylaxis and treatment of acute and chronic postherpetic neuralgia

“…W badaniach immunofluorescencyjnych skóry objętej procesem chorobowym widoczne jest uszkodzenie neuronów oraz wolnych zakończeń nerwowych, a także zwiększenie ekspresji receptorów związanych z bólem (ang. transient receptor potential cation channel subfamily V member 1 -TRPV1) [3][4][5]. Zniszczenie keratynocytów powoduje powstanie pęcherzyków śródnaskórkowych, które mogą się zlewać w większe pęcherze, pękać i tworzyć sączące, bolesne nadżerki.…”