Peripheral neural mechanisms of cutaneous hyperalgesia following mild injury by heat

Abstract

Pain thresholds in humans were determined for heat stimulations of the skin before and after a mild injury induced by a single conditioning stimulus (CS) of 50 degrees C and 100 sec duration. The same stimuli were delivered to the receptive fields of C fiber and A fiber mechanoheat-sensitive nociceptors (CMH and AMH nociceptors, respectively) and of low threshold warm and cold receptors in the anesthetized monkey and to the receptive fields of CMH nociceptors recorded percutaneously from the peroneal nerve of awake humans. Pain thresholds in normal skin were matched only by the response thresholds of CMH and not AMH nociceptors. Immediately following heat injury, some pain thresholds and CMH response thresholds were elevated, but by 5 to 10 min after the CS, pain and CMH thresholds were lowered to 2 to 6 degrees C below normal (hyperalgesia and nociceptor sensitization). No other type of cutaneous receptor studied exhibited changes in threshold similar to those observed for pain and for CMH nociceptors. The magnitude of hyperalgesia in humans and the magnitude of sensitization of CMH nociceptors in monkeys following heat injury were greater for hairy than for glabrous skin. The time course of the development of hyperalgesia was not altered by ischemia or conduction block in A fibers. The results support the conclusion that altered activity in CMH nociceptors is a major peripheral determinant of cutaneous hyperalgesia following a mild heat injury to the skin.

Modality-specific Somatosensory Changes in a Human Surrogate Model of Postoperative Pain

“…41 This would explain the long-lasting and robust hyperalgesia to heat in rodents 6,10 but not humans after incision (current study). The enhanced warm detection (warm hyperesthesia) after skin incision remained stable over the entire observation period of 72 h. However, sensitization of warm fibers has not been reported so far 30 and is thus unlikely to be the underlying mechanism. Alternatively, the warm hyperesthesia may be caused indirectly due to local warming by an increased blood flow 42 ; however, in rodents, local warming of the incision site is very discrete.…”

“…10,12 This fits well with the general finding that hyperalgesia to heat is typically restricted to the site of the injury in humans. 30,33,54 Moreover, we refrained from maintaining skin temperature because it is technically unfeasible to keep skin temperature constant at the incision side due to enhanced blood perfusion.…”

Two Types of C Nociceptors in Human Skin and Their Behavior in Areas of Capsaicin-Induced Secondary Hyperalgesia

“…The primary hyperalgesia at the site of capsaicin application features increased sensory responses to both mechanical and heat stimuli, attributed to sensitization of cutaneous nociceptor terminals, both of the common polymodal type (Campbell and Meyer 1983;LaMotte et al 1982LaMotte et al , 1983LaMotte et al , 1992Torebjörk et al 1984) and of the more recently described mechano-insensitive type of C nociceptor (Davis et al 1993;Meyer et al 1991;Schmelz et al 2000b;Schmidt et al 1995). The neural mechanisms underlying the secondary hyperalgesia in surrounding skin remain unclear.…”

Increased Nociceptive Input Rapidly Modulates Spinal GABAergic Transmission Through Endogenously Released Glutamate

“…The resulting pain intensity and duration often increase after the initial tissue or nerve damage. Tissue and peripheral nerve injury can sensitize primary afferents and spinal cord dorsal horn neurons, which results in secondary pain hypersensitivity (LaMotte et al 1982; Torebjork et al 1992; Woolf et al 1988). The release of inflammatory mediators from injured tissues and inflammatory cells, including prostaglandins (Martin et al 1987; Trebino et al 2003) and bradykinin (Liang et al 2001;Rueff and Dray 1993), can stimulate and sensitize nociceptors (peripheral sensitization).…”