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.

1 An increasing-temperature hot plate (ITHP) was introduced to measure the noxious heat threshold (45.370.31C) of unrestrained rats, which was reproducible upon repeated determinations at intervals of 5 or 30 min or 1 day. 2 Morphine, diclofenac and paracetamol caused an elevation of the noxious heat threshold following i.p. pretreatment, the minimum effective doses being 3, 10 and 200 mg kg À1 , respectively. 3 Unilateral intraplantar injection of the VR1 receptor agonist resiniferatoxin (RTX, 0.048 nmol) induced a profound drop of heat threshold to the innocuous range with a maximal effect (8 -101C drop) 5 min after RTX administration. This heat allodynia was inhibited by pretreatment with morphine, diclofenac and paracetamol, the minimum effective doses being 1, 1 and 100 mg kg À1 i.p., respectively. 4 The long-term sensory desensitizing effect of RTX was examined by bilateral intraplantar injection (0.048 nmol per paw) which produced, after an initial threshold drop, an elevation (up to 2.970.51C) of heat threshold lasting for 5 days. 5 The VR1 receptor antagonist iodo-resiniferatoxin (I-RTX, 0.05 nmol intraplantarly) inhibited by 51% the heat threshold-lowering effect of intraplantar RTX but not a,b-methylene-ATP (0.3 mmol per paw). I-RTX (0.1 or 1 nmol per paw) failed to alter the heat threshold either acutely (5 -60 min) or on the long-term (5 days). The heat threshold of VR1 receptor knockout mice was not different from that of wild-type animals (45.670.5 vs 45.270.41C). 6 In conclusion, the RTX-induced drop of heat threshold measured by the ITHP is a novel heat allodynia model exhibiting a high sensitivity to analgesics. British Journal of Pharmacology (2003) 139, 49 -58. doi:10.1038/sj.bjp.0705234 Keywords: Increasing-temperature hot plate; noxious heat threshold temperature; resiniferatoxin; heat allodynia; morphine; diclofenac; paracetamol; sensory desensitization; iodo-resiniferatoxin; a,b-methylene-ATP Abbreviations: I-RTX, iodo-resiniferatoxin; ITHP, increasing-temperature hot plate; a,b-meATP, a,b-methylene adenosine 5 0 -triphosphate; PPADS, pyridoxalphosphate-6-azophenyl-2 0 ,4 0 -disulphonic acid; RTX, resiniferatoxin; VR1, vanilloid receptor type 1

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