Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia

Abstract

1. A local cutaneous injury can produce primary hyperalgesia within the injured area and secondary hyperalgesia in the normal surrounding skin. An intradermal injection of capsaicin in humans causes intense pain and hyperalgesia to heat and to mechanical stimuli in the surrounding skin. Psychophysical studies in humans supported the conclusions that the hyperalgesia was predominantly the secondary type and depended on one set of neurons sensitizing another ("neurogenic hyperalgesia") and that the latter set of neurons is located in the central and not the peripheral nervous system. To further test this hypothesis and to search for peripheral neural mechanisms contributing to the pain and neurogenic hyperalgesia from a local injury, we performed neurophysiological experiments in the monkey (Macaca fascicularis) and recorded the responses of cutaneous primary afferent fibers to an intradermal injection of capsaicin and to mechanical and heat stimuli delivered before and after the injection. 2. Most C- and A-fiber mechanoheat-sensitive nociceptive afferent fibers (CMHs and AMHs, respectively) responded too weakly or transiently to capsaicin to account quantitatively for the magnitude of capsaicin pain. Of the known primary afferents tested with capsaicin injections, only the responses of heat-selective nociceptors could potentially account for the pain measured psychophysically in the human. In addition, a novel type of primary afferent--tentatively termed "chemonociceptive"--may have contributed as well. 3. Nociceptive fibers did not become sensitized to either mechanical or heat stimulation after an injection of capsaicin either outside, adjacent to, or inside the receptive field (RF); any changes that occurred could not explain the hyperalgesia to mechanical or heat stimuli observed in humans. 4. The depressed responsiveness ("desensitization") of both myelinated and unmyelinated nociceptive fibers in the monkey to heat and/or mechanical stimulation of the injection site after capsaicin was injected inside their RFs correlated with the analgesia observed at the capsaicin injection site in the human. 5. Capsaicin, topically applied to the RF in a vehicle of dimethyl sulfoxide or alcohol, excited CMHs and AMHs and enhanced the responses of some of these fibers to heat and/or to stroking the skin. In some cases, similar results were produced by the vehicle alone. However, capsaicin and not the vehicle lowered the thresholds of some CMHs to heat. Thus the sensitization of CMHs contributes to the primary hyperalgesia known to occur within the area of skin directly exposed to topically applied capsaicin.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of I A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

“…It is well known that nociceptors that are activated by capsaicin can become sensitized (Baumann et al 1991;Green 1989). To determine whether I A currents may contribute to this behavior, we have investigated how capsaicin modulates I A currents in TG neurons.…”

“…Depending on its concentration, length of application, and interstimulus interval, it can produce sensitization, hyperalgesia, or desensitization (Baumann et al 1991;Dessirier et al 2000;Green 1989). Capsaicin's activation of nociceptors arises from the depolarization produced by the opening of vanilloid receptors (whose K 1/2 approximately 1 M at physiological pH).…”

“…The initial painful sensation after capsaicin application arises from the selective activation of vanilloid receptors in capsaicin-sensitive nociceptors that leads to depolarization and the generation of action potentials (APs) (Baumann et al 1991;Gold et al 1996a;Heyman and Rang 1985;LaMotte et al 1991;Williams and Zieglganberger 1982). Our goal is to investigate mechanisms by which capsaicin can initiate hyperalgesia in rat trigeminal ganglion (TG) neurons.…”

The Relationship between Cutaneous C Fibre Type and Antidromic Vasodilatation in the Rabbit and the Rat

“…Microneurography studies in the peroneal nerve of man have shown that 6% of C fibre afferents are heat nociceptor units (Schmidt, Schmelz, Forster, Ringkamp, Torebj ork & Handwerker, 1995). In monkey hairy skin it is reported that heat nociceptor afferents make up 7% of C fibres (Baumann, Simone, Shain & LaMotte, 1991), and in monkey glabrous skin they make up 5·5% of nociceptive C fibres (Georgopoulos, 1976). It will be of interest to see the relative roles that the heat and polymodal nociceptor units play in generating neurogenic inflammation in primate skin.…”

Cortical Neurophysiological Modification after Peripheral Neuronal Sensitization

“…Baumann reported that cutaneous application of capsaicin induced hyper-responses in unmyelinated small nerve fibers as well as axonal reflex-related neurogenic hyperalgesia. In addition to this peripheral process, alteration of primary afferents induces sensitization of second order spino-thalamic tract (STT) neurons, a major noxious pain pathway, known to have an influence on pain perception 5) . Sluka et al reported that, STT neurons demonstrated an increased background activity and increased response to innocuous stimuli for approximately 20 minutes following capsaicin injection 6) .…”