Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice

Abstract

Capsaicin-sensitive, TRPV1 (transient receptor potential vanilloid 1) receptor-expressing primary sensory neurons exert local and systemic efferent effects besides the classical afferent function. The TRPV1 receptor is considered a molecular integrator of various physico-chemical noxious stimuli. In the present study its role was analysed in acute nociceptive tests and chronic neuropathy models by comparison of wild-type (WT) and TRPV1 knockout (KO) mice. The formalin-induced acute nocifensive behaviour, carrageenan-evoked inflammatory mechanical hyperalgesia and partial sciatic nerve lesion-induced neuropathic mechanical hyperalgesia were not different in WT and KO animals. Acute nocifensive behaviour after intraplantar injection of phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), was absent in TRPV1 KO animals showing that PKC activation elicits nociception exclusively through TRPV1 receptor sensitization/activation. Thermal hyperalgesia (drop of noxious heat threshold) and mechanical hyperalgesia induced by a mild heat injury (51 degrees C, 15s) was smaller in KO mice suggesting a pronociceptive role for TRPV1 receptor in burn injury. Chronic mechanical hyperalgesia evoked by streptozotocin-induced diabetic and cisplatin-evoked toxic polyneuropathy occurred earlier and were greater in the TRPV1 KO group. In both polyneuropathy models, at time points when maximal difference in mechanical hyperalgesia between the two groups was measured, plasma somatostatin concentrations determined by radioimmunoassay significantly increased in WT but not in TRPV1 KO mice. It is concluded that sensitization/activation of the TRPV1 receptor plays a pronociceptive role in certain models of acute tissue injury but under chronic polyneuropathic conditions it can initiate antinociceptive counter-regulatory mechanisms possibly mediated by somatostatin released from sensory neurons.

Histopathological Changes of Streptozotocin-induced Painful Diabetes and Antihyperalgesic Effect of Capsaicin Cream in Rats

“…There are some reports suggesting the underlying mechanisms of hyperalgesia in this model 13,[20][21][22][23] . In one of the mechanisms, expression of VR1 are observed in capsaicin-insensitive A-fiber DRG neurons of STZ diabetic mice suggested as a cause of the hyperalgesia.…”

Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I

“…These responses were initially taken as evidence for a role of TRPV1 in normal nociception (Tominaga et al, 1998). Recently, however, evidence from physiological and behavioral assessments of TRPV1-null mice has indicated that TRPV1 is not required for detecting noxious heat (Woodbury et al, 2004), but plays a significant role in pathological nociception (e.g., hyperalgesia) associated with tissue injury and inflammation (Caterina et al, 2000;Davis et al, 2000;Bolcskei et al, 2005;Pogatzki-Zahn et al, 2005). This is believed to occur through posttranslational changes in the sensitivity and membrane density of TRPV1 as well as transcriptional changes in TRPV1 expression in response to a variety of molecules released during injury or inflammation including NGF, bradykinin, and PGE2 (Lopshire and Nicol, 1998;Shu and Mendell, 2001;Bonnington and McNaughton, 2003;Sugiuar et al, 2004;Zhuang et al, 2004;Zhang et al, 2005;Stein et al, 2006;Zhu and Oxford, 2007).…”

Attenuation of neuropathy-induced allodynia following intraplantar injection of pregabalin

“…The corresponding plate temperature was considered the noxious heat threshold. 25 Changes of the locomotor function of the neuropathic rats were evaluated by rotarod testing (Acceler rota-rod for rats 7750; Ugo Basile, Comerio-Varese, Italy). The rats with neuropathic pain were acclimatized to the revolving drum, and they were desensitized to manual handling to ameliorate any stress during testing.…”