Synaptic mechanisms in nociception: emerging targets for centrally-acting analgesics

Abstract

The lifetime incidence of chronic pain in Western populations is almost 50%, but current pharmacological treatments are poorly tolerated and ineffective against some types of pain, giving rise to a demand for new analgesic drugs. The primary symptoms of chronic pain are allodynia, hyperalgesia and spontaneous pain, all of which indicate a high level of excitability in central pain processing systems. Recent basic research has identified a bewildering number of molecules as actual or putative mediators of spinal hyperexcitability, and the main thrust of the present article is that antagonists for these molecules should provide new antihyperalgesic or analgesic treatments. Ionotropic glutamate receptors (particularly N-methyl-D-aspartate [NMDA], but including other calciumpermeable receptors), in conjunction with voltage-gated calcium channels, permit ingress of calcium ions into spinal dorsal horn neurones. In addition, group I metabotropic glutamate (mGlu) and tachykinin NK 1 and NK 3 receptors give rise to release of calcium from intracellular stores. In theory, antagonists for any of these receptors ought to be antihyperalgesic, but recent experience in clinical trials with NK 1 receptor blockers has been disappointing. More encouragingly, non-selective antagonists for glutamate NMDA receptors are effective in all types of chronic pain in humans, albeit with side effects that are unacceptable. The recognition that NMDA receptors exist in multiple subtypes, and that the NR2B subtype is found (among only a few other sites) in the superficial dorsal horn of the spinal cord in rat, suggests that selective antagonists for these receptors may offer analgesia without the attendant problems of non-selective drugs. Selective antagonists for other calcium-permeable glutamate receptors, mGlu group I, NK 3 and CGRP1 receptors may also have a future as antihyperalgesic agents, but all are at a very early stage of development. At present, the best hope for a powerful broad-spectrum antihyperalgesic lies with the NMDA receptor subtypes.

Glutamate and tachykinin receptors in central sensitization of withdrawal reflexes in the decerebrated rabbit

“…The effectiveness of CP‐101,606 in reducing sensitization cannot be attributed to its depressor action (see above). As noted by others, antagonists selective for NR2B‐subunit bearing NMDA receptors could provide a viable target for antihyperalgesic drugs that would be free from some of the more debilitating side‐effects of the complete antagonists (Boyce et al 1999; Merchant et al 1999; Clarke, 2000; Chizh et al 2001).…”

“…One of the suggestions put forward to explain this failure has been that inactivation of just one component of the many transmitter systems activated in parallel by noxious stimuli is insufficient to produce a clear antihyperalgesic action (Hill, 2000; Clarke, 2000). The present data support this view, which lay behind the final experiment in which blockade of NK 1 and NK 3 receptors was combined with antagonism at NR2B subunit containing NMDA receptors.…”

“…Glutamate is known to be a key transmitter in the sensitization of nociceptive circuits (Baranauskas & Nistri, 1998; Clarke, 2000), and N‐methyl‐D‐aspartate (NMDA) receptors in particular have been shown to have a key role. NMDA receptor antagonists effectively block central sensitization of reflexes in rats (Woolf & Thompson, 1991) and human trials of clinically available antagonists such as ketamine and dextromethorphan have demonstrated good efficacy in all types of chronic pain states, albeit with a predictable range of side‐effects including cognitive deficits (Sang, 2000; Fisher et al 2000; Eide, 2000).…”

“…There is considerable evidence to support a role for tachykinins in the development of chronic pain (Clarke, 2000; Salter, 2002). Most attention has focused on the NK 1 receptor, which has been implicated in most rodent‐based models of chronic pain (Luo & Wiesenfeld‐Hallin, 1995; Parsons et al 1996; Liu & Sandkuhler, 1997; Ma & Woolf, 1997; De Felipe et al 1998; Herrero et al 2000; Gonzalez et al 2000; Cahill & Coderre, 2002).…”

“…For a positive control, the effects of non‐selective blockade of spinal NMDA receptors has also been studied. Finally, as sensitization involves parallel activation of many different receptors (Hill, 2000; Clarke, 2000), we have also studied the effects of combined blockade of all tachykinin receptors. Some of these data have been published as abstracts (Harris et al 2002; Harris et al 2003).…”