Pharmacologic blockade

At present, two conceptually different (but not mutually exclusive) therapeutic strategies are being pursued in the vanilloid field one is to use optimized TRPVl agonists to desensitize (in practice, defunctionalize) capsaicin-sensitive nerves [1, 21] and the other is to employ small molecule antagonists for the pharmacological blockade of TRPVl [7, 8]. The first approach is time-proven, but is riddled by known side-effects such as pain [1], as well as emerging concerns such as impaired control of cancerous growth [22]. 

In diabetic rats, TRPVl is enhanced on myelinated fibres and is hyperphos-phorylated by PKC [127]. In accordance with these findings, anti-TRPVl antiserum was shown to ameliorate pain in a murine model of diabetic neuropathy [128]. In humans, the density of TRPVl-positive nerve fibres is increased in women with chronic breast pain [129] and with vulvodynia [19]. Disruption of TRPV 1 gene causes attenuation of bone cancer pain in mice [130]. Pharmacological blockade of TRPVl by agonists relieved pain in AIDS patients [131]. 

An alternative approach to pharmacological blockade of LTP is to drive the level of synaptic plasticity to a theoretical maximum by repeatedly inducing LTP experimentally (often termed saturation ). Experimental induction of maximal LTP occluded the formation of new spatial memories (McNaughton et al., 1986 Castro et al., 1989). There was mixed success in replicating these... 

Nowadays a broad spectrum of quite specific blood pressure lowering drugs is available which restricts the use of ganglion blockade. There are only a few situations in which the pharmacological blockade autonomous ganglia is clinically useful hypertensive emergencies, controlled hypotension in neurosurgery and in the treatment of pulmonary edema. 

Booij LH. Neuromuscular transmission and its pharmacological blockade. Part 2 Pharmacology of neuromuscular blocking agents. B Pharm World Sci 1997 19(1) 13-34. 

Rupniak NM, Carlson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, de Felipe C, Hunt SP, Oates B, Wheeldon A (2001) Comparison of the phenotype of NKIR-/- mice with pharmacological blockade of the substance P (NKl) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 12 497-508 Saffroy M, Torrens Y, Glowinski J, Beaujouan JC (2001) Presence of NK2 binding sites in the rat brain. J Neurochem 79 985-996... 

Guscott M, Bristow LJ, Hadingham K, et al. Genetic knockout and pharmacological blockade studies of the 5-HT(7) receptor suggest therapeutic potential in depression. Neuropharmacology 2005 48 492-502. 

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