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PubMed1999

Descending facilitatory influences from the rostral medial medulla mediate secondary, but not primary hyperalgesia in the rat.

Prolonged nociceptive input following peripheral injury results in hyperalgesia (enhanced response to a noxious stimulus), which is thought to occur as a consequence of sensitization of primary afferent nociceptors and enhanced excitability of spinal dorsal horn nociceptive neurons (central sensitization). Since there is often an expansion of hyperalgesia to tissue adjacent, and even distant from the site of injury (secondary hyperalgesia), it is thought that this phenomenon primarily involves mechanisms of central modulation/plasticity. In contrast, hyperalgesia observed at the site of tissue injury (primary hyperalgesia) involves peripheral mechanisms. In the current study, we examined the relative contribution of descending nociceptive facilitatory systems from the rostral medial medulla to enhanced behavioral nociceptive responses in models of primary and secondary hyperalgesia in awake rats. The effect of bilateral rostral medial medulla lesions produced by the soma-selective neurotoxin ibotenic acid was determined in three different models of cutaneous thermal hyperalgesia following peripheral inflammation: (i) intraplantar injection of carrageenan into the hindpaw (model of primary hyperalgesia); (ii) intra-articular injection of carrageenan/kaolin into the knee of the hind leg (model of secondary hyperalgesia); and (iii) topical application of mustard oil to the hind leg (model of secondary hyperalgesia). Compared with sham lesion animals, a bilateral lesion of the rostral medial medulla completely blocked thermal hyperalgesia in the two models of secondary hyperalgesia (intra-articular carrageenan/kaolin injection into the knee and topical mustard oil application to the hind leg), but was ineffective in blocking facilitation of the thermal paw withdrawal response in the model of primary hyperalgesia (intraplantar carrageenan injection into the hindpaw). These results suggest that primary and secondary hyperalgesia are differentially modulated in the CNS, and support the notion that descending nociceptive facilitatory influences from the rostral medial medulla significantly contribute to secondary, but not primary, hyperalgesia.

Animals↗
PubMed1997

Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation.

1. Following induction of acute inflammation by intraarticular injection of kaolin and carrageenan into the knee joint in rats, there was a significant decrease in the withdrawal latency to radiant heat applied to the paw (i.e. heat hyperalgesia), an increased joint circumference and increased joint temperature. 2. A neurokinin1 (NK1) receptor antagonist (CP-99,994, 10 mM) had no effect on the paw withdrawal latency when it was administered spinally through a microdialysis fibre before the induction of inflammation. Pretreatment with a NK2 receptor antagonist (SR48968, 1 mM) administered spinally through the microdialysis fibre prevented the heat hyperalgesia from developing in the early stages of the inflammation. 3. Post-treatment through the microdialysis fibre with the NK1 receptor antagonist (0.01-10 mM) was effective in reversing the heat hyperalgesia. In contrast, post-treatment spinally with the NK2 receptor antagonist (0.01-1 mM) had no effect on the heat hyperalgesia. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 4. Pretreatment systemically with the NK1 receptor antagonist (30 mg kg-1) had no effect on the heat hyperalgesia or pain-related behaviour ratings where 0 is none and 5 is non weight bearing and complete avoidance of limb contact. Pretreatment with a NK2 receptor antagonist (10 mg kg-1) systemically prevented the heat hyperalgesia and pain-related behaviour ratings from developing in the early stages of the inflammation. The inactive stereoisomers of NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 5. Post-treatment systemically with either the NK1 (0.1-30 mg kg-1) or the NK2 (0.1-10 mg kg-1) receptor antagonist resulted in a dose-dependent reversal of the heat hyperalgesia. Pain-related behaviour ratings were reduced by post-treatment only with the NK1 receptor antagonist. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the behavioural responses. 6. Direct pretreatment of the knee joint with either the NK1 (30 mg) or the NK2 (10 mg) receptor antagonist prevented the heat hyperalgesia from developing without affecting joint swelling. The inactive stereoisomers of the NK1 receptor antagonist, CP100,263, or the NK2 receptor antagonist, SR48965, administered at the same doses, had no effect on the joint inflammation or the heat hyperalgesia. 7. There appears to be a differential role for the spinal tachykinin receptors in the development and maintenance of the heat hyperalgesia associated with acute joint inflammation. The NK2 receptors appear to be activated early in the development of the heat hyperalgesia and NK1 receptors are involved in the maintenance of the heat hyperalgesia. 8. Peripherally, both NK1 and NK2 receptors are involved in the development of heat hyperalgesia and pain-related behaviour ratings induced by acute inflammation.

Animals↗
PubMed1991

Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms.

1. Psychophysical studies were made, in humans, of the sensory characteristics and underlying mechanisms of the hyperalgesia (often termed "secondary hyperalgesia") that occurs in uninjured skin surrounding a local cutaneous injury. The hyperalgesia was characterized by lowered pain thresholds and enhanced magnitude of pain to normally painful stimuli. The "injury" was produced by a single intradermal injection of 10 microliters of 100 micrograms of capsaicin, the algesic substance in hot chili peppers. 2. On injection of capsaicin into the volar forearm, the subjects experienced intense burning pain, accompanied immediately by the formation of three areas of hyperalgesia surrounding the injection site. The largest mean area (55 cm2) was hyperalgesic to a normally painful punctate stimulation of the skin. Nested within this was an area of tenderness to gentle stroking (38 cm2) and a much smaller area of hyperalgesia to heat (2 cm2). An area of analgesia to pinprick, approximately 4 mm in diameter and centered on the injection site, developed within minutes and typically disappeared within 24 h. The hyperalgesia to heat and to stroking disappeared within 1-2 h, whereas the hyperalgesia to punctate stimuli, although gradually decreasing in area, lasted from 13 to 24 h. 3. The radial spread of the mechanical hyperalgesia (to punctate and stroking stimuli) away from the injury was dependent on neural activity and not produced, for example, by algesic substances transported away from the injury. The injection of capsaicin into a small area of anesthetized skin did not produce hyperalgesia in the surrounding, unanesthetized skin. Also, the hyperalgesia in normal skin readily crossed a tight arm band that blocked the circulation of blood and lymph. 4. The spread of mechanical hyperalgesia away from the injury was peripherally mediated via cutaneous nerve fibers because it was blocked by a thin mediolateral strip of cutaneous anesthesia placed 1 cm away from the capsaicin injection site. Hyperalgesia developed normally on the capsaicin side of the strip but not on the other side. 5. Heat stimulation of the skin that produced pain that was equivalent in magnitude and time course to that produced by an injection of capsaicin (10 micrograms) resulted in much smaller areas of mechanical hyperalgesia. It was postulated that there exist special chemosensitive primary afferent nerve fibers that are more effective in producing mechanical hyperalgesia than are the known thermo- and mechanosensitive nociceptive nerve fibers. 6. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2004

Amiodarone decreases heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain.

UNLABELLED: Lidocaine is effective in controlling ventricular dysrhythmia and neuropathic pain. Amiodarone, like lidocaine, has sodium channel blocking properties. In the present study we explore whether amiodarone has a similar effect as lidocaine on the heat, cold, and mechanical hyperalgesia seen in the rat model of neuropathic pain. Ten male Sprague-Dawley rats were anesthetized. Four loose ligatures were placed on the sciatic nerve of the right hindpaw. A sham operation was performed on the contralateral hindpaw (control). Heat hyperalgesia was determined by comparing each paw withdrawal latency to heat stimulation (radiant heat source, 50 degrees C). Cold hyperalgesia was assessed with acetone application. Mechanical hyperalgesia was determined by comparing the mechanical threshold in the ligated and control hind paws using calibrated von Frey filaments. Amiodarone was intraperitoneally administered at doses of 1, 5, 10, 20, 50, and 100 mg/kg after the development of hyperalgesia. The animals were tested for hyperalgesia before and 1, 3, and 24 h after the administration of a single dose of amiodarone. Intrathecal catheters were implanted in 5 new rats, and amiodarone 5 mg/kg was injected. Testing for heat, mechanical, and cold hyperalgesia was performed similarly in the intrathecal amiodarone administration group. Amiodarone produces statistically significant decreases of heat, cold, and mechanical hyperalgesia after intraperitoneal administration. Results are statistically significant at 10 mg/kg (heat hyperalgesia), 20 mg/kg (mechanical hyperalgesia), and 100 mg/kg (cold hyperalgesia) intraperitoneally. Hyperalgesia returns 24 h after a dose. The intrathecal administration of amiodarone produces a nonstatistically significant reduction of hyperalgesia. Amiodarone seems to have a similar effect as lidocaine on the hyperalgesia seen in the rat model of neuropathic pain. As the half-life of amiodarone is significantly longer that that of lidocaine (mean, 53 days versus 90 min) in humans, it may have the potential to provide a longer lasting (and perhaps more effective) effect than lidocaine on neuropathic pain states. IMPLICATIONS: Amiodarone was found to produce a statistically significant decrease in heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain after intraperitoneal injection. Considering its long half-life in humans, amiodarone has the potential to provide long lasting pain relief in neuropathic pain states.

Amiodarone↗
PubMed2003

Tumor implantation in mouse humerus evokes movement-related hyperalgesia exceeding that evoked by intramuscular carrageenan.

In this paper we compare two innovative models of movement-related pain: tumor-induced nociception following implantation of fibrosarcoma cells into bone and muscle inflammation-induced nociception following injection of the irritant carrageenan into muscle. Importantly, using the grip force test, an assay of movement-related hyperalgesia, both non-malignant and malignant pain are examined in parallel. Movement-related hyperalgesia, known clinically as a specific type of 'breakthrough pain', is a common feature of bone cancer and is thought to be a predictor of poor response to conventional analgesic pharmacotherapy (Bruera et al., 1995, J. Pain Symptom. Manage. 10 (1995) 348; Mercadaute et al., 1992, Pain 50 (1992) 151; Pain 81 (1999) 129). Implantation of NCTC 2472 sarcoma cells in both humeri or injection of carrageenan (4%) in both triceps of C3H/He mice produced apparent forelimb hyperalgesia that was not associated with mechanical hyperalgesia in the forepaw, whereas carrageenan at 6 and 8% did evoke significant cutaneous hyperalgesia of the forepaw as well. Control groups receiving implants of vehicle or no treatment at all did not manifest this forelimb hyperalgesia. B6C3/F1 mice implanted with non-lysis-inducing G3.26 melanoma cells or vehicle did not manifest significant hyperalgesia when compared to B6C3/F1 mice receiving fibrosarcoma cells, indicating a dependence on bone involvement for induction of hyperalgesia in this model. Histological examination at days 3, 7, and 10 post-implantation showed a clear correlation of tumor growth-induced bone destruction with behavioral hyperalgesia. Morphine was more potent in decreasing the maximal hyperalgesia induced by carrageenan than that induced by tumor implantation. Acutely administered morphine (3-100mg/kg, i.p.) attenuated peak hyperalgesia of carrageenan-injected mice (ED(50) 6.9 mg/kg) and tumor-bearing mice (ED(50) 23.9 mg/kg) in a dose-related manner with a difference in potency of 3.5. Tumor-implanted mice with a level of hyperalgesia comparable to that induced by carrageenan required almost three times more morphine (ED(50) 18.5mg/kg) for equivalent attenuation of forelimb hyperalgesia. These animal models of movement-related hyperalgesia may aid in discerning the peripheral and central mechanisms underlying pain that accompanies bone metastases and distinguishing it from the pain associated with muscular inflammation. Importantly, they may also aid in predicting differences in analgesic efficacy in different types of musculoskeletal pain.

Analgesics, Opioid↗
PubMed1997

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.

Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain ('wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1 degree burn injury covering 12.5 cm2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a 'wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia ('wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the 'wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and 'wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect 'wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.

Adult↗
PubMed2000

Secondary heat, but not mechanical, hyperalgesia induced by subcutaneous injection of bee venom in the conscious rat: effect of systemic MK-801, a non-competitive NMDA receptor antagonist.

Subcutaneous (s.c.) administration of bee venom into the plantar surface of one hind paw in rats has been found to produce an immediate single phase of persistent spontaneous nociceptive responses (continuously flinching, licking or lifting the injected paw) for 1-2 h accompanied by a 72-96 hour period of primary heat and mechanical hyperalgesia in the injection site and a spread of heat, but not mechanical, hyperalgesia in the non-injected hind paw (Chen et al., 1999b). To gain insight into the underlying mechanisms of the bee venom-induced hyperalgesia in particular, we further identified a heat, but not mechanical, hyperalgesia in an area (paw pad) distant from the injection site induced by s.c. injection of bee venom into the posterior leg 0.8-1.2 cm proximal to the heel measured by paw withdrawal reflex to radiant heat or von Frey monofilament stimuli in conscious rats. In the bee venom-treated hind limb, however, significant reduction in both thermal latency and mechanical threshold of withdrawal reflex was identified for a period of more than 96 h in the heel with a similar characteristic to the primary heat and mechanical hyperalgesia identified in the injection site previously. The time course of the heat hyperalgesia identified in the paw pad of the bee venom-treated side was shorter and lasted for less than 48 h, which was in parallel with the reduction in thermal latency of the withdrawal reflex identified in the non-injected hind paw. Moreover, pre- or post-treatment with a single dose of MK-801 (0.01 mg/kg, i.p.), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, completely blocked the occurrence, and reversed the established process of the heat hyperalgesia identified in either the bee venom-treated or non-treated paw pads, while the same treatments with the drug did not produce any influence upon the development and maintaining of the heat and mechanical hyperalgesia identified in the heel of the injected hind limb. Taken together with our previous results following s.c. intraplantar bee venom injection, we conclude that: (1) in addition to the well-identified primary heat and mechanical hyperalgesia in the injection site and its adjacent area, s.c. bee venom is also able to produce a secondary heat hyperalgesia in a region distant from the injection site which has a similar characteristic to the contralateral heat hyperalgesia; (2) NMDA receptors are involved in either development or maintenance of the secondary and the contralateral heat hyperalgesia, but without any role in those processes of the primary heat and mechanical hyperalgesia; (3) the secondary heat hyperalgesia seen in the injected hind limb is likely to share the same neural mechanisms with that identified in the non-injected side via co-activation of NMDA receptors.

Animals↗
PubMed1994

Peripheral and central mechanisms of NGF-induced hyperalgesia.

Mechanisms underlying the hyperalgesia induced by a single systemic injection of nerve growth factor (NGF) in adult rats were studied in vivo. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals which had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5-hydroxytryptamine receptor antagonists (ICS 205-930 and methiothepin) also developed an NGF-induced thermal hyperalgesia, but onset was delayed by more than 3 h. In the presence of ICS 205-930 or methiothepin the early component NGF-induced hyperalgesia was reversed and the animals responded with an initial hypoalgesia to the thermal stimuli. Whereas these results indicate a peripheral mechanism for the initial thermal hyperalgesia, the later phase (7 h-4 days after NGF) appeared to be centrally maintained, since it could be selectively blocked by the non-competitive NMDA receptor antagonist MK-801. In contrast to the almost immediate thermal hyperalgesia following a single injection of NGF, a significant mechanical hyperalgesia began only after a 7 h latency. This NGF-induced mechanical hyperalgesia was not blocked by any of the treatments that attenuated the thermal hyperalgesia, indicating that a separate mechanism may be involved. Additional electrophysiological experiments showed that NGF-induced hyperalgesia was not maintained by an increased amount of spontaneous activity in C-fibres. A final result showed that endogenous release of NGF in a model of acute inflammation (complete Freund's adjuvant-induced inflammation) may be involved in the development of thermal hyperalgesia, since it could be blocked by concomitant treatment with anti-NGF antisera. These data indicate that NGF-induced thermal and mechanical hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism involving the degranulation of mast cells, whereas the late component involves central NMDA receptors. In contrast, the NGF-induced mechanical hyperalgesia seems to be independent of mast cell degranulation or central NMDA receptor sites.

Animals↗
PubMed1993

Nerve growth factor-induced hyperalgesia in the neonatal and adult rat.

Recently, we have shown that the interaction between NGF and sensory neurons in early postnatal periods is restricted to nociceptive afferents (Ritter et al., 1991; Lewin et al., 1992a; Ritter and Mendell, 1992). Here we show that administration of excess NGF to neonatal or mature animals can lead to a profound behavioral hyperalgesia. Neonatal NGF treatment (postnatal day 0-14) resulted in a profound mechanical hyperalgesia that persisted until the animals had reached maturity (6 weeks of age). This hyperalgesia could be explained by an NGF-mediated sensitization of A delta nociceptive afferents to mechanical stimuli. This peripheral sensitization wore off with a time course similar to that of the behavior hyperalgesia. Treatment of animals from the second postnatal week until 5 weeks of age (juveniles) led to a very similar behavioral hyperalgesia; however, there was no corresponding sensitization of A delta nociceptors to mechanical stimuli. Finally, one group of adult animals (5 weeks old) was treated daily with single injections of NGF for between 1 and 4 d. Within 24 hr after the first NGF injection these animals developed a mechanical hyperalgesia of the same magnitude seen after neonatal and juvenile NGF treatments. No sensitization of A delta nociceptive afferents was observed in these animals. In addition to the mechanical hyperalgesia, the animals also developed a heat hyperalgesia after one injection of NGF. The heat hyperalgesia was apparent within 15 min after the injection; however, signs of mechanical hyperalgesia were not seen until 6 hr after the injection. In conclusion, it appears that the NGF-induced mechanical hyperalgesia is brought about by different mechanisms in neonatal and adult rats. Furthermore, in adult animals the NGF-induced mechanical and heat hyperalgesia also appear to be attributable to two different mechanisms. The mechanical hyperalgesia may be due to central changes (see Lewin et al., 1992b), whereas the heat hyperalgesia is likely to result at least in part from the sensitization of peripheral receptors to heat.

Aging↗
PubMed1988

Characterization of the arachidonic acid metabolites mediating bradykinin and noradrenaline hyperalgesia.

It has been suggested that bradykinin (BK) and norepinephrine (NE) induce hyperalgesia, indirectly, by stimulating the production of prostaglandin products of the cyclo-oxygenase pathway of arachidonic acid metabolism. However, the specific PGs that mediate the hyperalgesic effects of BK and NE are unknown. Two endogenous PGs, prostaglandin E2 (PGE2) and prostacyclin (PGI2) are known to produced hyperalgesia. Since the hyperalgesic effects of PGE2 and PGI2 can be distinguished by the duration of the hyperalgesia they induce, we have compared the duration of BK and NE hyperalgesia with those of PGE2 and PGI2. To further address the type of PG mediating BK and NE hyperalgesia, we have evaluated the ability of SC19220, a PG-receptor antagonist, to distinguish the hyperalgesia induced by PGE2 and PGI2. BK induces hyperalgesia with duration similar to that of PGE2. NE induces hyperalgesia with duration similar to that of PGI2. SC19220, at low doses, antagonizes PGE2 and BK hyperalgesia but not PGI2 and NE hyperalgesia. These data are compatible with the suggestion that the prostaglandin products mediating BK and NE hyperalgesia differ, BK hyperalgesia being mediated by PGE2 and NE hyperalgesia by PGI2.

Animals↗
PubMed2005

Differential coding of hyperalgesia in the human brain: a functional MRI study.

Neuropathic pain can be both ongoing or stimulus-induced. Stimulus-induced pain, also known as hyperalgesia, can be differentiated into primary and secondary hyperalgesia. The former results from sensitization of peripheral nociceptive structures, the latter involves sensitization processes within the central nervous system (CNS). Hypersensitivity towards heat stimuli, i.e. thermal hyperalgesia, is a key feature of primary hyperalgesia, whereas secondary hyperalgesia is characterized by hypersensitivity towards mechanical (e.g. pin-prick) stimulation. Using functional magnetic resonance imaging (fMRI), we investigated if brain activation patterns associated with primary and secondary hyperalgesia might differ. Thermal and pin-prick hyperalgesia were induced on the left forearm in 12 healthy subjects by topical capsaicin (2.5%, 30 min) application. Equal pain intensities of both hyperalgesia types were applied during fMRI experiments, based on previous quantitative sensory testing. Simultaneously, subjects had to rate the unpleasantness of stimulus-related pain. Pin-prick hyperalgesia (i.e. subtraction of brain activations during pin-prick stimulation before and after capsaicin exposure) led to activations of primary and secondary somatosensory cortices (S1 and S2), associative-somatosensory cortices, insula and superior and inferior frontal cortices (SFC, IFC). Brain areas activated during thermal hyperalgesia (i.e. subtraction of brain activations during thermal stimulation before and after capsaicin exposure) were S1 and S2, insula, associative-somatosensory cortices, cingulate cortex (GC), SFC, middle frontal cortex (MFC) and IFC. When compared to pin-prick hyperalgesia, thermal hyperalgesia led to an increased activation of bilateral anterior insular cortices, MFC, GC (Brodmann area 24' and 32') and contralateral SFC and IFC, despite equal pain intensities. Interestingly, stronger activations of GC, contralateral MFC and anterior insula significantly correlated to higher ratings of the stimulus-related unpleasantness. We conclude that thermal and mechanical hyperalgesia produce substantially different brain activation patterns. This is linked to different psychophysical properties.

Adult↗
PubMed2006

Primary and secondary hyperalgesia can be differentiated by postnatal age and ERK activation in the spinal dorsal horn of the rat pup.

Noxious C-fibre stimulation produces increased sensitivity within the injured area (primary hyperalgesia), and a surrounding zone of secondary hyperalgesia. As significant changes in nociceptive processing occur during development, we compared C-fibre induced primary and secondary hyperalgesia in rat pups aged 3, 10 and 21 postnatal (P) days. Hyperalgesia was measured by electromyography flexion reflex recordings following mustard oil or capsaicin at the site of (primary hyperalgesia), or distant to (secondary hyperalgesia) hindpaw mechanical stimuli. Primary hyperalgesia was induced at all postnatal ages, whereas secondary hyperalgesia could not be demonstrated at P3 but was evident at P10 and P21. At P3, extracellular signal-regulated kinase (ERK) protein is present in the dorsal horn, but hindpaw capsaicin produced minimal ERK activation restricted to the fourth lumbar segment. At P21, capsaicin induced intense phosphoERK expression in the superficial dorsal horn throughout several lumbar segments, consistent with the spread of secondary hyperalgesia. Intrathecal administration of the MEK (ERK kinase) inhibitor PD98059 prevented mustard oil and capsaicin-induced secondary hyperalgesia at P21, but had no effect on primary hyperalgesia at P3 or P21. These results provide evidence that primary and secondary hyperalgesia are differentially modulated during development. Furthermore, since ERK activation is required for secondary hyperalgesia, phosphoERK expression can be used to map the spatial distribution of neuronal activation in the spinal cord. Understanding changing responses to injury in the developing nervous system is important for clinical paediatric practice, and will enhance our ability to target the most effective site with a developmentally appropriate analgesic regime.

Aging↗
PubMed2002

Experimental incision-induced pain in human skin: effects of systemic lidocaine on flare formation and hyperalgesia.

In order to try to gain a better understanding of the mechanisms of post-operative pain, this study was designed to psychophysically determine physiological and pharmacological characteristics of experimental pain induced by a 4-mm-long incision through the skin, fascia and muscle in the volar forearm of humans. In experiment 1, the subjects (n=8) were administered lidocaine systemically (a bolus injection of 2mg/kg for a period of 5 min followed by an intravenous infusion of 2mg/kg/h for another 40 min), and then the incision was made. In experiment 2, cumulative doses of lidocaine (0.5-2mg/kg) were systemically injected in the subjects (n=8) 30 min after the incision had been made, when primary and secondary hyperalgesia had fully developed. Spontaneous pain was assessed using the visual analog scale (VAS). Primary hyperalgesia was defined as mechanical pain thresholds to von Frey hair stimuli (from 7 to 151 mN) in the injured area. The area of secondary hyperalgesia to punctate mechanical stimuli was assessed using a rigid von Frey hair (151 mN). Flare formation was assessed in the first experiment using a laser doppler imager (LDI). Pain perception was maximal when the incision was made and then rapidly disappeared within 30 min after the incision had been made. Primary hyperalgesia was apparent at 15 min after the incision had been made and remained for 2 days. The incision resulted in a relatively large area of flare formation immediately after the incision had been made. The area of flare began to shrink within 15 min and was limited to a small area around the injured area at 30 min after incision. Secondary hyperalgesia was apparent at 30 min after incision and persisted for 3h after incision and then gradually disappeared over the next 3h. In experiment 1, pre-traumatic treatment with systemic lidocaine suppressed primary hyperalgesia only during the first 1h after the incision had been made. The lidocaine suppressed the development of flare formation without affecting the pain rating when the incision was made. The development of secondary hyperalgesia continued to be suppressed after completion of the lidocaine infusion. In experiment 2, post-traumatic treatment with lidocaine temporarily suppressed primary as well as secondary hyperalgesia that had fully developed; however, the primary and secondary hyperalgesia again became apparent after completion of the lidocaine administration. These findings suggest that pre-traumatic treatment with lidocaine reduces the excessive inputs from the injured peripheral nerves, thus suppressing development of flare formation and secondary hyperalgesia through peripheral and central mechanisms, respectively. Pre-traumatic treatment with lidocaine would temporarily stabilize the sensitized nerves in the injured area, but the nerves would be sensitized after completion of the administration. Post-traumatic treatment with lidocaine reduced primary and secondary hyperalgesia that had fully developed. However, the finding that the suppressive effect of lidocaine on secondary hyperalgesia was temporary suggests that the development and maintenance of secondary hyperalgesia are caused by different mechanisms.

Adult↗
PubMed2006

Morphine hyperalgesia in mice is unrelated to opioid activity, analgesia, or tolerance: evidence for multiple diverse hyperalgesic systems.

Hyperalgesia following chronic morphine treatment is thought to be a response to opioid receptor activation and analgesia and contribute to the development of analgesic tolerance. Here, the relationship between these variables was studied in mice tested for nociceptive sensitivity on the tail-withdrawal test during chronic infusion of various morphine doses. Hyperalgesic onset was preceded by dose-dependent analgesia except for the lowest morphine dose, which caused hyperalgesia 6 h after the start of infusion. Morphine ED50 values obtained at various infusion intervals demonstrated both analgesic tolerance in the absence of hyperalgesia and hyperalgesia in the absence of tolerance. Continuous opioid receptor antagonism using naltrexone pellets abolished analgesia during continuous morphine administration, transiently potentiated hyperalgesia, and revealed differences in hyperalgesic onset between morphine infusion doses. Acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 attenuated hyperalgesia in naltrexone-treated mice, demonstrating a role for this receptor in morphine hyperalgesia unrelated to its effects upon morphine analgesia. In mice where hyperalgesia subsided after continuous infusion of the highest morphine dose (i.e., hyperalgesic adaptation), hyperalgesia was restored after infusing the lower but not higher morphine dose. In addition, acute injection of morphine-3beta-glucoronide (M3G) caused hyperalgesia that was cross-adaptive with the lower morphine dose only. The data demonstrate that morphine hyperalgesia is independent of prior or concurrent opioid receptor activity or analgesia and is unrelated to analgesic tolerance. Furthermore, the lack of hyperalgesic cross-adaptation between high and low morphine doses, and their differential cross-adaptation with M3G hyperalgesia, also suggests distinct morphine dose-dependent hyperalgesic systems.

Analgesia↗
PubMed2003

Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision.

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. We further determined if Ca(2+) permeable AMPA/kainate receptors are important for secondary hyperalgesia after gastrocnemius incision and for pain behaviors indicating primary hyperalgesia and guarding behavior after plantar incision. Withdrawal thresholds (WTs) to punctate mechanical stimuli were assessed by applying calibrated monofilaments to the plantar hind paw before gastrocnemius incision. WTs were tested again 2 h after gastrocnemius incision and again after intrathecal (IT) injection of either dizocilpine maleate (MK-801), 2-amino-5-phosphonovaleric acid (AP5), 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), or Joro spider toxin (JSTX). The doses used were: MK-801 (vehicle, 15, 30, 40 nmol), AP5 (vehicle, 10, 30 nmol), NBQX (vehicle, 5, 10 nmol), and JSTX (vehicle, 2, 5, 9 nmol). In the same rats, WTs were tested on postoperative day 2 before and after the same drugs were injected again. In other rats, WTs to monofilaments and response frequencies to a non-punctate mechanical stimulus or guarding behaviors were determined before, 1 h after plantar incision was made, and assessed again after JSTX (9 nmol or vehicle) was administered IT. Secondary mechanical hyperalgesia after gastrocnemius incision was dose-dependently blocked by NBQX but was only marginally affected by AP5 or MK-801. Only secondary mechanical hyperalgesia was reversed by JSTX; primary mechanical hyperalgesia and guarding behavior were unchanged. These results indicate that spinal sensitization contributing to behaviors for secondary hyperalgesia after incision requires Ca(2+) permeable AMPA/kainate receptors. The data further demonstrate that behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting behaviors for primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.

Animals↗
PubMed2003

Spatial and temporal profiles of flare and hyperalgesia after intradermal capsaicin.

Intradermal injection of capsaicin induces a region of visual flare (neurogenic inflammation) and regions with modality specific hyperalgesia. Their temporal and spatial profiles have been studied to elucidate the mechanism behind neurogenic inflammation and hyperalgesia. Until today, the flare response has mainly been quantified by visual inspection. However, recent developments of thermography and laser-Doppler flowmetry have facilitated quantitative measurement of the neurogenic inflammation. The purpose of the present study was (1). to measure the temporal and spatial profiles of neurogenic inflammation and hyperalgesia induced by capsaicin by using thermography/laser-Doppler flowmetry and various sensory tests, and (2). to correlate the parameters related to neurogenic inflammation with the areas of secondary hyperalgesia. Eight healthy volunteers were injected intradermally with 250 microg of capsaicin. Five minutes after the injection, temperature and blood flow were measured by thermography and a laser-Doppler flowmetry, and followed by assessment of visual flare and hyperalgesia. Punctate hyperalgesia, stroking hyperalgesia, and heat hyperalgesia were assessed by von Frey hair, cotton swab, and radiant heat stimulator, respectively. This procedure was repeated 30 and 60 min after the injection. A significant increase in blood flow and temperature was detected by laser-Doppler flowmetry and thermography (F=102.08, P<0.001, and F=8.46, P=0.002, respectively). Throughout the experiment, the areas of visual flare, stroking hyperalgesia, and punctate hyperalgesia were covered by the area of significantly increased blood flow detected 5 min after the injection. The intensity of pain to heat stimuli significantly increased over time at the distal site and the proximal site (P<0.05). However, there was no significant difference between the pain intensity to radiant heat stimuli inside/outside the area of punctate hyperalgesia. These results seem to indicate that a possible contribution of neurogenic inflammation to secondary hyperalgesia (especially to radiant heat stimuli) must be reconsidered.

Capsaicin↗
PubMed1996

Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin.

A psychophysical investigation was carried out to examine whether heat hyperalgesia exists within the secondary mechanical hyperalgesia zone surrounding a capsaicin injection site on hairy skin. A non-contact laser stimulator was used to deliver temperature controlled stimuli to sites within and outside the zone of mechanical hyperalgesia. Heat testing was carried out before and after the intradermal injection of 50 micrograms of capsaicin into the volar forearm. The zones of mechanical hyperalgesia to punctate and stroking stimuli and the region of flare were also mapped after the capsaicin injection. Heat pain thresholds inside the secondary mechanical hyperalgesic zone were not significantly different from thresholds outside the secondary mechanical hyperalgesia zone. In addition, pain ratings to an ascending series of heat stimuli delivered inside the zone of secondary hyperalgesia were not significantly different from pain ratings outside the zone of secondary hyperalgesia. Thus, there was no evidence for heat hyperalgesia within the zone of secondary hyperalgesia to punctate mechanical stimuli. Though the areas of punctate and stroking hyperalgesia were correlated, no correlation existed between the magnitude of capsaicin evoked pain and the areas mechanical hyperalgesia to punctuate and stroking stimuli or the area of flare. This suggests that independent mechanisms may mediate evoked pain, central sensitization that leads to mechanical hyperalgesia, and axon reflexive flare.

Analysis of Variance↗
PubMed2002

Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat.

Bradykinin-induced mechanical hyperalgesia is sympathetically dependent and B(2)-type bradykinin receptor-mediated in the rat; however, a sympathetically independent component of bradykinin hyperalgesia is shown after subdiaphragmatic vagotomy. We evaluated the mechanism of this bradykinin-induced sympathetic-independent mechanical hyperalgesia. The dose-response curve for bradykinin mechanical hyperalgesia in sympathectomized plus vagotomized rats was similar in magnitude to that for sympathetically dependent bradykinin hyperalgesia in normal rats. Although bradykinin mechanical hyperalgesia was mediated by the B(2)-type bradykinin receptors after sympathectomy plus vagotomy, it had a much more rapid latency to onset. This hyperalgesia was significantly attenuated by inhibition of protein kinase A but not protein kinase C, similar to the hyperalgesia produced by prostaglandin E(2), an agent that directly sensitizes primary afferent nociceptors. However, unlike prostaglandin E(2)-induced mechanical hyperalgesia in normal rats, after sympathectomy plus vagotomy, bradykinin-induced hyperalgesia was not attenuated by inhibition of nitric oxide synthesis. Peripheral administration of a mu opioid agonist, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin, significantly attenuated bradykinin mechanical hyperalgesia after sympathectomy plus vagotomy. These data suggest that after sympathectomy plus subdiaphragmatic vagotomy, bradykinin acts directly on primary afferents to produce mechanical hyperalgesia via a novel protein kinase A-dependent signaling mechanism.

Journal Article↗