Topical Glutamate Receptor Antagonists

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Within the dorsal spinal cord, both ionotropic glutamate receptors (N-methyl-D-aspartate, NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA) and metabotropic glutamate receptors are involved in nociceptive signaling and central sen-sitization in chronic pain conditions. Both the systemic and spinal administration of multiple classes of glutamate receptor antagonists have been observed to produce analgesia in a variety of persistent pain models, and although their potential as analgesics has been investigated, they have a tendency to produce unacceptable side effects. Perhaps the most extensively used glutamate receptor antagonist in human practice is ketamine.

More recently it has been appreciated that multiple glutamate receptors are also expressed on peripheral nerve terminals, and that these may contribute to peripheral nociceptive signaling (Table 8.1).

Table 8.1 Excitatory and inhibitory influences on peripheral nerve activity by mediators released by tissue injury and inflammation and by agents acting on neuroreceptors.

Inhibitory influences

Excitatory influences

Opioids (p, S, k)

Prostanoids (EP, IP)

GABA (GABAb)

a2-adrenoreceptor (a2A)

a2-adrenoreceptor (a2C)

Bradykinin (B1, B2)

Orphinan (ORL1)

Glutamate (NMDA, AMPA, KA)

Adenosine (A1)

Histamine (H1)

Somatostatin

Acetylcholine (N)

Cannabinoids (CB1, CB2)

Serotonin (5HT1, 5HT2, 5HT3, 5HT4)

Adenosine (A2A, A3)

ATP (P2X3)

Tachykinins (NK1, NK2)

Nerve growth factor (TrkA)

Ionotropic and metabotropic glutamate receptors are present on membranes of unmyelinated peripheral axons and axon terminals in the skin, and peripheral inflammation increases the proportions of both unmyeli-nated and myelinated nerves expressing ionotropic glutamate receptors. Local injections of NMDA and non-NMDA glutamate receptor agonists to the rat hindpaw or knee joint enhance pain behaviors generating hyperalgesia and allodynia. Intraplanter injection of metabotropic glutamate receptor agonists produces similar actions. On the contrary, local administration of antagonists of both ionotropic and metabotropic receptors inhibits pain behavior evoked by kaolin and carrageenan injected into the knee joint.

Inflammation of the hindpaw or the knee joint produces a local release of glutamate that appears to originate from A and C fibers. An additional indirect mechanism, via activation of glutamate receptors on sympathetic afferents to release norepinephrine and other substances from postganglionic efferents (e.g., ATP, neuropeptide Y), can occur as NMDA, AMPA, and KA receptors are also present on postganglionic sympathetic efferents, and inflammation enhances the expression of such receptors. Collectively, these results suggest that the involvement of local release of glutamate receptors and activation of both ionotropic and metabo-tropic glutamate receptors in inflammatory pain in particular, and raises the possibility that peripheral application or possibly topical formulations of such agents may be useful as analgesics. Whether topical application results in sufficient dermal transfer of the drug or whether intradermal or subcutaneous injection is required is not yet clear. It is also possible that peripheral glutamate receptors play a significant role in peripheral pain signaling in neuropathic pain (as occurs at spinal sites), but this contention is as yet unsubstantiated.

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