Review article Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia Horacio Vanegas a, * , Hans-Georg Schaible b a Instituto Venezolano de Investigaciones Cienti®cas (IVIC), Apartado 21827, Caracas 1020-A, Venezuela b Institut fu Èr Physiologie, Friedrich-Schiller-Universita Èt, Jena, Teichgraben 8, D-07740 Jena, Germany Received 8 June 1999; received in revised form 8 September 1999; accepted 9 September 1999 Abstract High-threshold voltage-dependent calcium channels enable calcium ions to enter neurons upon depolarization and thereby in¯uence synaptic mediator/receptor systems, membrane excitability levels, second and third messenger concentration, and gene expression. These phenomena underlie several processes including those of normal nociception and of hyperalgesia and allodynia. The present article deals with the role of spinal L-, N- and P/Q-type calcium channels in short-lasting nociception as well as in the hyperalgesia and allodynia elicited by chemical irritants of peripheral nociceptors, in¯ammatory and mechanical lesions of peripheral tissues, and lesions of peripheral nerves. The studies summarized herein are based on the spinal delivery of speci®c antagonists to high-threshold calcium channels, and reveal that blockade of L-type, P/Q-type and, particularly, N-type channels can prevent, attenuate, or both, subjective pain as well as primary and/or secondary hyperalgesia and allodynia in a variety of experimental and clinical conditions. q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Calcium channels; Spinal cord; Pain; Hyperalgesia; In¯ammation; Neuropathy 1. Introduction Physical, chemical and in¯ammatory damage in periph- eral tissues is a source of persistent nociceptive messages and gives rise to increased excitability of nociceptive neurons in the spinal and trigeminal dorsal horns (central sensitization). Damage to peripheral nerves is also a source of abnormal input to the central nervous system and a cause of dorsal horn hyperexcitability. These central changes contribute to the symptoms which appear in humans under such circumstances, namely, spontaneous pain, an elevated sensation of pain when previously painful stimuli are applied to the lesioned tissue (primary hyperalgesia) or to adjacent, normal tissues (secondary hyperalgesia), and a sensation of pain or `discomfort' (allodynia) upon the appli- cation of a stimulus which would normally elicit a sensation of, e.g. touch. In experiments on animals, the spontaneous attitudes and the reactions elicited by peripheral damage or by speci®c stimuli are generally taken to be the expression of similar sensations as in humans, and are thus given simi- lar names. The neuronal changes that underlie these symp- toms and behavioral manifestations involve processes in which calcium ions play a key role. Extracellular calcium gains access to the intracellular milieu by way of several paths, one of which is that of speci®c membrane channels gated by depolarization, i.e. voltage-dependent calcium channels (VDCCs). Among these, those channels which are activated only by relatively large depolarizations, i.e. high-threshold VDCCs, have recently been the subject of considerable research concerning short-lasting nociception as well as the hyperalgesia and allodynia induced by periph- eral lesions. High-threshold VDCCs of the L-, N- and P/Q- type can be blocked by speci®c antagonists (see Table 1), and the present review deals with the effects that the spinal application of these antagonists alone (that is, without other drugs) has upon pain-related phenomena in various experi- mental and clinical settings. Only those studies aimed at VDCCs located in the spinal cord will be considered, and at the end a summary table (Table 2) will be presented and some general comments will be offered. 2. High-threshold voltage-dependent calcium channels VDCCs are involved in numerous functions of neurons such as release of neurotransmitters, voltage-dependent Pain 85 (2000) 9±18 0304-3959/00/$20.00 q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. PII: S0304-3959(99)00241-9 www.elsevier.nl/locate/pain * Corresponding author. Tel.: 149-3641-938811; fax: 149-3641- 938812. E-mail address: hvanegas@mti-n.uni-jena.de (H. Vanegas)