Secondary hyperalgesia

Increased responsiveness to noxious stimuli is termed hyperalgesia. It occurs following injury or disease and encompasses enhanced responses as well as reduced thresholds to a given noxious stimulus. Primary hyperalgesia occurs in the damaged area whereas secondary hyperalgesia occurs in the area surrounding it. 

Clinical manifestation Primary hyperalgesia, allodynia, spontaneous pain Secondary hyperalgesia, allodynia, spontaneous pain, aberrantly referred pain ... 

Nociceptive neurons in the spinal cord as well as in higher centres such as the thalamus and cortex can also undergo alterations in activity following chronic peripheral changes and trauma (Table 1). These changes are typically long-term in nature and lead to the clinical syndromes of centrally maintained pain (secondary hyperalgesia, allodynia, spontaneous pain). Alterations... 

Primary hyperalgesia occurs within the zone of injury and is caused by changes at the injury site itself. Secondary hyperalgesia occurs around the zone of injury and results from neuroplasticity and remodelling. 

The uncompetitive NMDA receptor antagonist ketamine has been available for clinical use as an anaesthetic for 40 years (Domino et al. 1965). Ketamine is effective in various animal models of hyperalgesia and allodynia and has been reported to have antinociceptive effects in some of these models at doses devoid of obvious side-effects. Others, however, have reported that the effects of ketamine are only seen at doses producing ataxia (see Parsons 2001 for review). Ketamine reportedly inhibits the area of secondary hyperalgesia induced by chemical (Park et al. 1995) or thermal stimuli (Ilkjaer et al. 1996 Warncke et al. 1997) and inhibits temporal siunmation of repeated mechanical (Warncke et al. 1997) and electrical stimuli (Arendtnielsen et al. 1995 Andersen et al. 

Wang Y, Small DL, Stanimhovic DB, et al (1997) AMPA receptor-mediated regulation of a Gi-protein in cortical neurons. Nature 389 502-504 Warncke T, Jorimi E, Stubhaug A (1997) Local treatment with the N-methyl-n-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett 227 1-4... 

Warncke, T., Stubhaug, A., Jorum, E. Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man a double-blind, cross-over comparison with morphine and placebo, Pain 1997, 72, 99-106. 

A second aCGRP-deficient mouse was produced by Hoff et al. (1998) in order to study the role of calcitonin. CGRP mice are born normally, are fertile and live a normal life span. These mice were tested in a model of chronic arthritis, where a mixture of kaolin/carrageenan was injected into the knee joint and in comparison to wild type mice failed to develop secondary hyperalgesia (Zhang et al., 2001). 

Ziegler, E. A., Magerl, W., Meyer, R. A., and Treede, R. D. (1999). Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 122(Pt 12), 2245-2257. 

In a randomized, double-blind study, 14 patients who underwent elective surgery for correction of bilateral arthritic deformities of the feet received 15 ml of 0.9% saline containing diamorphine 2.5 mg into the cannula in one foot and 15 ml of saline into the other foot (6). Intravenous regional diamorphine did not improve postoperative pain relief or secondary hyperalgesia. There were no significant adverse effects. 

Sjolund KF, Segerdahl M, Sollevi A. Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflanunatoiy pain. Anesth Analg 1999 88(3) 605-10. 

Torebjork HE, Lundberg LE, LaMotte RH (1992) Central changes in processing of mechanore-ceptive input in capsaicin- induced secondary hyperalgesia in humans. J Physiol 448 765-780... 

A study in 11 healthy subjects found that the combination of ketamine and morphine almost abolished windup-like pain (progressive increase in pain intensity on repeated stimulation) in a skin bum injury. This effect was not found with either dmg alone. Further, ketamine done, but not morphine reduced the area of secondary hyperalgesia of the local bum and increased the pain threshold, but the combination did not appear to enhance this effect. The reduction of wind-up pain may be due to ketamine-induced prevention of acute tolerance to morphine. ... 

Hyperalgesia is defined by the International Association for the Study of Pain (lASP) as an increased response to a stimulus which is normally painful . Primary hyperalgesia or peripheral sensitization reflects the activation and sensitization of nociceptive A delta and polymodal C-fiber terminal endings within the injured area. Secondary hyperalgesia, or central sensitization, involves spinal neuroplasticity and facilitation... 

Related to peripheral release of Intracellular or humoral noxious mediators Secondary hyperalgesia... 

A-fiber nociceptors mediate secondary hyperalgesia to punctate stimuli through a second pathway. 

The activation of spinal extracellular signaling-regulated kinase-1 and -2 (ERKl, ERK2) is also required for secondary hyperalgesia [8]. Noxious activation of ionotropic, metabotropic, and tyrosine kinase receptors in dorsal horn neurons activates protein kinase A (PKA) and protein kinase C (PKC), leading to the production of ERK. Hyperalgesia after thermal stimulation is mediated by non-NMDA receptors. The thermal stimulus model demonstrates distinct protein kinase involvement downstream from spinal non-NMDA receptor activation. Jones et al. [9]... 

Serra J, Campero M, Bostock H, Ochoa J. Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia. 

Walker SM, Meredith-Middleton J, Lickiss T, Moss A, Fitzgerald M. Primary and secondary hyperalgesia can be differentiated by postnatal age and ERK activation in the spinal dorsal horn of the rat pup. Pain 2007 128(1-2) 157-168. 

Jones TL, Lustig AC, Sorkin LS. Secondary hyperalgesia in the post-operative pain model is dependent on spinal calcium/calmodulin-dependent protein kinase II activation. Anesth Analg 2007 105 1650-1656. 

Jones DL, Sorkin LS. Systemic gabapentin and S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia. Brain Res 1998 810(1-2) 93-99. 

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