Ion Channels & Novel Analgesic Targets

Ion Channels & Novel Analgesic Targets

Even the most severe acute pain (lasting hours to days) can usu-ally be well controlled—with significant but tolerable adverse effects—using currently available analgesics, especially the opi-oids. Chronic pain (lasting weeks to months), however, is not very satisfactorily managed with opioids. It is now known that in chronic pain, receptors on sensory nerve terminals in the periph-ery contribute to increased excitability of sensory nerve endings (peripheral sensitization). The hyperexcitable sensory neuron bombards the spinal cord, leading to increased excitability and synaptic alterations in the dorsal horn (central sensitization). Such changes appear to be important in chronic inflammatory and neuropathic pain states.

In the effort to discover better analgesic drugs for chronic pain, renewed attention is being paid to synaptic transmission in nociception and peripheral sensory transduction. Potentially important ion channels associated with these processes in the periphery include members of the transient receptor potential family such as the capsaicin receptor, TRPV1 (which is acti-vated by multiple noxious stimuli such as heat, protons, and products of inflammation) as well as TRPA1, activated by inflam-matory mediators; and P2X receptors (which are responsive to purines released from tissue damage). Special types of tetrodo-toxin-resistant voltage-gated sodium channels (Nav 1.7, 1.8,1.9) are uniquely associated with nociceptive neurons in dorsalroot ganglia. Lidocaine and mexiletine, which are useful in some chronic pain states, may act by blocking this class of chan-nels. Genetic polymorphisms of Nav 1.7 are associated with either absence or predisposition to pain. Because of the impor-tance of their peripheral sites of action, therapeutic strategies that deliver agents that block peripheral pain transduction or transmission have been introduced in the form of transdermal patches and balms. Such products that specifically target periph-eral capsaicin receptors and sodium channel function are becoming available.

Ziconotide, a blocker of voltage-gated N-type calciumchannels, is approved for intrathecal analgesia in patients with refractory chronic pain. It is a synthetic peptide related to the marine snail toxin ω-conotoxin, which selectively blocks these calcium channels. Gabapentin/pregabalin, anticonvulsant analogs of GABA , are effective treatments for neuropathic (nerve injury) pain and inflammatory pain acting at voltage-gated calcium channels containing the α₂δ₁ sub-unit. N-methyl-D-aspartate (NMDA) receptors appear to play a very important role in central sensitization at both spinal and supraspinal levels. Although certain NMDA antagonists have demonstrated analgesic activity (eg, ketamine), it has been difficult to find agents with an acceptably low profile of adverse effects or neurotoxicity. However, ketamine at very small doses appears to improve analgesia and reduce opioid requirements under conditions of opioid tolerance. In fact, ketamine applied topically has been claimed to have analgesic effects. GABA and acetylcholine (through nicotinic receptors) appear to control the central synaptic release of several trans-mitters involved in nociception. Nicotine itself and certain nicotine analogs cause analgesia, and their use for postopera-tive analgesia is under investigation. Finally, work on cannabi-noids and vanilloids and their receptors suggest that D9- tetrahydrocannabinol, which acts primarily on CB₁can-nabinoid receptors, can synergize with μ-receptor analgesics and interact with the TRPV1 capsaicin receptor to produce analgesia under certain circumstances.

As our understanding of peripheral and central pain trans-duction improves, additional therapeutic targets and strate-gies will become available. Combined with our present knowledge of opioid analgesics, a “multimodal” approach to pain therapy is emerging, which allows the use of complemen-tary compounds resulting in improved analgesia with fewer adverse effects.