Different Mechanisms of Development and Maintenance of Experimental Incision-induced Hyperalgesia in Human Skin

2002 ◽  
Vol 97 (3) ◽  
pp. 550-559 ◽  
Author(s):  
Mikito Kawamata ◽  
Hiroaki Watanabe ◽  
Kohki Nishikawa ◽  
Toshiyuki Takahashi ◽  
Yuji Kozuka ◽  
...  
Keyword(s):  
Human Study ◽  
Nerve Fibers ◽  
Spontaneous Pain ◽  
Mechanical Stimuli ◽  
Secondary Hyperalgesia ◽  
Incision Site ◽  
Short Period ◽  
Lidocaine Injection ◽  
Primary Hyperalgesia ◽  
Double Blinded

Background To determine the mechanisms of postoperative pain, the effects of local anesthesia on development and maintenance of surgical incision-induced hyperalgesia were evaluated in a crossover, double-blinded, placebo-controlled human study using 17 subjects. Methods An experimental 4-mm-long incision through skin, fascia, and muscle was made in the volar forearm of each subject. In experiment 1, 1% lidocaine or saline in a volume of 0.2 ml was subcutaneously injected into the incision site pretraumatically and posttraumatically. In experiment 2, a 5-cm-long strip of skin was subcutaneously injected with 0.2 ml of 1% lidocaine near the incision site pretraumatically and posttraumatically. Flare, spontaneous pain, and primary and secondary hyperalgesia to punctate mechanical stimuli were assessed after the incision had been made. Results Pretraumatic lidocaine injection prevented the occurrence of spontaneous pain and development of flare formation that was found surrounding the incision site immediately (1 min) after the incision had been made. The lidocaine suppressed primary hyperalgesia more effectively than did posttraumatic block, but only for the first 4 h after the incision. The preincision block prevented development of secondary hyperalgesia, whereas posttraumatic block did not significantly affect the fully developed secondary hyperalgesia. The area of flare formation and the area of secondary hyperalgesia did not extend over the strip of the skin that had been pretraumatically anesthetized, whereas the posttraumatic block did not significantly reduce the area of fully developed secondary hyperalgesia. Conclusions Pretraumatic injection of lidocaine reduces primary hyperalgesia more effectively than does posttraumatic injection, but only for a short period after incision. The spread of secondary hyperalgesia is mediated peripheral nerve fibers, but when secondary hyperalgesia has fully developed, it becomes less dependent on or even independent of peripheral neural activity originating from the injured site.

Reduction of Postincisional Allodynia by Subcutaneous Bupivacaine

2005 ◽  
Vol 103 (1) ◽  
pp. 113-125 ◽  
Author(s):  
Adriana M. Duarte ◽  
Eva Pospisilova ◽  
Erin Reilly ◽  
Florence Mujenda ◽  
Yoshihiro Hamaya ◽  
...  
Keyword(s):  
Skin Incision ◽  
Mechanical Stimuli ◽  
Secondary Hyperalgesia ◽  
Sprague Dawley ◽  
Hairy Skin ◽  
Incision Site ◽  
Sprague Dawley Rats ◽  
Graded Response ◽  
Primary Hyperalgesia ◽  
Response Score

Background An incision of hairy skin of the rat's back provides a new model for postincisional pain to determine the importance of cutaneous anesthesia. Methods Male Sprague-Dawley rats were anesthetized with sevoflurane and given a 0.6-ml subcutaneous injection of bupivacaine (0.25%) under the incision site or the medial lumbar dorsum or at the nuchal midline, 30 min before a 1.0-cm skin incision. Mechanical stimuli (von Frey hairs, 18-250 mN) were applied to measure nociception, indicated by twitching of local subcutaneous muscles, the cutaneus trunci muscle reflex. A graded response score, averaging the twitches weighted by their vigor, or a population response score, measuring the fraction of rats that showed any response, was assessed for 3 days before and over 7 days after incision. von Frey hairs were applied 0.5 cm from the incision to test primary hyperalgesia and 2.0 cm contralateral to the incision for secondary hyperalgesia. Results Incision induced responses to stimuli that had no effect on intact skin (allodynia) and also enhanced responses to forces that normally gave less than the full reflex (hyperalgesia). Hyperalgesia was present 30 min after surgery, peaked at 3-6 h, and persisted through the week; allodynia had a similar onset but was briefer. Both changes were transiently reversed by subcutaneous morphine (2.5 mg/kg intraperitoneal). Subcutaneous bupivacaine (0.25%), injected preoperatively at the incision site and anesthetizing skin for 2-3 h, suppressed primary allodynia for 1 week but had no effect on hyperalgesia. Secondary allodynia was obliterated, and secondary hyperalgesia attenuated by this treatment. Bupivacaine injected subcutaneously at the nuchal midline before surgery was also effective in abbreviating primary and secondary allodynia, with no signs of sedation, ataxia, or preconvulsive behavior. Conclusions Incision of rat hairy skin changes pain responses, similar to pain in humans. Preincisional subcutaneous bupivacaine selectively suppresses and shortens allodynia for times far outlasting its local anesthesia, an effect largely from systemic actions.

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

2004 ◽  
Vol 91 (6) ◽  
pp. 2770-2781 ◽  
Author(s):  
Jordi Serra ◽  
Mario Campero ◽  
Hugh Bostock ◽  
José Ochoa
Keyword(s):  
Electrical Stimulation ◽  
Discrete Series ◽  
Intradermal Injection ◽  
Repetitive Stimulation ◽  
Mechanical Stimuli ◽  
Secondary Hyperalgesia ◽  
Stimulation Protocol ◽  
C Fiber ◽  
Primary Hyperalgesia ◽  
Stimulation Of

Peripheral nociceptor sensitization is accepted as an important mechanism of cutaneous primary hyperalgesia, but secondary hyperalgesia has been attributed to central mechanisms since evidence for sensitization of primary afferents has been lacking. In this study, microneurography was used to test for changes in sensitivity of C nociceptors in the area of secondary hyperalgesia caused by intradermal injection of capsaicin in humans. Multiple C units were recruited by electrical stimulation of the skin at 0.25 Hz and were identified as discrete series of dots in raster plots of spike latencies. Nociceptors slowed progressively during repetitive stimulation at 2 Hz for 3 min. According to their response to mechanical stimulation, nociceptors could be classified as either mechano-sensitive (CM) or mechano-insensitive (CMi). These two nociceptor subtypes had different axonal properties: CMi units slowed by 2% or more when stimulated at 0.25 Hz after a 3-min pause, whereas CM units slowed by <1%. This stimulation protocol was used before capsaicin injection to identify nociceptor subtype without repeated probing, thus avoiding possible mechanical sensitization. Capsaicin, injected 10–50 mm away from the site of electrical stimulation, had no effect on any of 29 CM units, but induced bursts of activity in 11 of 15 CMi units, after delays ranging from 0.5 to 18 min. The capsaicin injections also sensitized a majority of the CMi units, so that 11 of 17 developed immediate or delayed responsiveness to mechanical stimuli. This sensitization may contribute a peripheral C fiber component to secondary hyperalgesia.

Primary and Secondary Hyperalgesia in a Rat Model for Human Postoperative Pain 

1999 ◽  
Vol 90 (3) ◽  
pp. 863-872 ◽  
Author(s):  
Peter K. Zahn ◽  
Timothy J. Brennan
Keyword(s):  
Postoperative Pain ◽  
Rat Model ◽  
Radiant Heat ◽  
Mechanical Stimulus ◽  
Mechanical Stimuli ◽  
Secondary Hyperalgesia ◽  
Transitional Area ◽  
Withdrawal Threshold ◽  
Plantar Aspect ◽  
Primary Hyperalgesia

Background Previously, the authors developed and characterized a rat model for postoperative pain to learn more about pain produced by incisions. In this study, the responses to heat and mechanical stimuli were evaluated directly on or adjacent to the incision and at varying distances from the incision. Methods Rats were anesthetized with halothane and incisions were made at different locations in the plantar aspect of the foot. The response frequency to a blunt mechanical stimulus, the withdrawal threshold to von Frey filaments (15-522 mN), and the withdrawal latency to radiant heat were measured. Rats were tested before surgery, 2 h later, and then daily through postoperative day 9. Results After plantar incision, persistent hyperalgesia was observed immediately adjacent to or directly on the incision to punctate and blunt mechanical stimuli, respectively. The withdrawal threshold to punctate stimuli applied 1 cm from the incision was decreased through postoperative day 1. In a transitional area, between the distant and adjacent sites, the withdrawal threshold was intermediate and the duration of hyperalgesia was transient. Heat hyperalgesia was persistent but present when the stimulus was applied to the site of injury but not to a distant site. Conclusion Robust primary hyperalgesia to punctate and blunt mechanical stimuli was present. Hyperalgesia distant to the wound, or secondary hyperalgesia, occurred in response to punctate mechanical stimuli, was short-lived, and required greater forces. These results suggest that the most persistent pain behaviors in this model are largely primary hyperalgesia.

scholarly journals Recent Advances in Biomarkers and Regenerative Medicine for Diabetic Neuropathy

2021 ◽  
Vol 22 (5) ◽  
pp. 2301
Author(s):  
Yoshikai Fujita ◽  
Tatsufumi Murakami ◽  
Akihiro Nakamura
Keyword(s):  
Diabetic Neuropathy ◽  
Target Gene ◽  
Pathological Condition ◽  
Nerve Fibers ◽  
Nerve Degeneration ◽  
Limb Amputation ◽  
Sensory Impairment ◽  
Mechanical Stimuli ◽  
Pathological Conditions ◽  
The Relationship

Diabetic neuropathy is one of the most common complications of diabetes. This complication is peripheral neuropathy with predominant sensory impairment, and its symptoms begin with hyperesthesia and pain and gradually become hypoesthesia with the loss of nerve fibers. In some cases, lower limb amputation occurs when hypoalgesia makes it impossible to be aware of trauma or mechanical stimuli. On the other hand, up to 50% of these complications are asymptomatic and tend to delay early detection. Therefore, sensitive and reliable biomarkers for diabetic neuropathy are needed for an early diagnosis of this condition. This review focuses on systemic biomarkers that may be useful at this time. It also describes research on the relationship between target gene polymorphisms and pathological conditions. Finally, we also introduce current information on regenerative therapy, which is expected to be a therapeutic approach when the pathological condition has progressed and nerve degeneration has been completed.

scholarly journals Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

2008 ◽  
Vol 109 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Birgit Kraft ◽  
Nathalie A. Frickey ◽  
Rainer M. Kaufmann ◽  
Marcus Reif ◽  
Richard Frey ◽  
...  
Keyword(s):  
Inflammatory Pain ◽  
Animal Studies ◽  
Analgesic Efficacy ◽  
Spontaneous Pain ◽  
Heat Pain ◽  
Secondary Hyperalgesia ◽  
Double Blind ◽  
Pain Thresholds ◽  
Healthy Female ◽  
Cannabis Extract

Background Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. Methods The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Results Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. Conclusion To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy

1992 ◽  
Vol 67 (6) ◽  
pp. 1562-1573 ◽  
Author(s):  
J. Palecek ◽  
V. Paleckova ◽  
P. M. Dougherty ◽  
S. M. Carlton ◽  
W. D. Willis
Keyword(s):  
Dynamic Range ◽  
Background Activity ◽  
Thermal Stimulation ◽  
Spontaneous Pain ◽  
Mechanical Stimuli ◽  
Spinothalamic Tract ◽  
High Background ◽  
Threshold Temperatures ◽  
Thermal Stimuli ◽  
Stimulation Of

1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

Differential Effect of Ketamine and Lidocaine on Spontaneous and Mechanical Evoked Pain in Patients with Nerve Injury Pain

2006 ◽  
Vol 104 (3) ◽  
pp. 527-536 ◽  
Author(s):  
Hanne Gottrup ◽  
Flemming W. Bach ◽  
Gitte Juhl ◽  
Troels S. Jensen
Keyword(s):  
Nerve Injury ◽  
Molecular Mechanisms ◽  
Channel Blocker ◽  
Spontaneous Pain ◽  
Sodium Channel Blocker ◽  
Signaling System ◽  
Aspartate Receptor ◽  
Ongoing Pain ◽  
Double Blinded ◽  
Crossover Experiments

Background The mechanisms underlying neuropathic pain are incompletely understood. Targeting specific molecular mechanisms in the pain signaling system may assist in understanding key features in neuropathic pains such as allodynia. This study examined the effect of systemically administered ketamine, an N-methyl-D-aspartate receptor antagonist and lidocaine, a sodium channel blocker, on spontaneous pain, brush-evoked pain, and pinprick-evoked pain in patients with nerve injury pain. Methods Twenty patients participated in two randomized, double-blinded, placebo-controlled, crossover experiments in which they, on four different days, received a 30-minute intravenous infusion of ketamine (0.24 mg/kg), lidocaine (5 mg/kg), or saline. Ongoing pain, pain evoked by brush and repetitive pinprick stimuli, and acetone was measured before, during, and after infusion. Results Ketamine significantly reduced ongoing pain and evoked pain to brush and pinprick, whereas lidocaine only reduced evoked pain to repetitive pinprick stimuli. In individual patients, there was no correlation between the pain-relieving effect of lidocaine and ketamine on ongoing or mechanically evoked pains. Conclusions N-methyl-D-aspartate receptor-linked systems and sodium channels are involved in generation and maintenance of pain in patients with peripheral nerve injury. It is likely that ongoing pain as well as mechanical hyperalgesia in individual patients is dependent on several separate molecular mechanisms.

Protein Kinase C γ Interneurons Mediate C-fiber–induced Orofacial Secondary Static Mechanical Allodynia, but Not C-fiber–induced Nociceptive Behavior

2016 ◽  
Vol 124 (5) ◽  
pp. 1136-1152 ◽  
Author(s):  
Cedric Peirs ◽  
Nathalie Bourgois ◽  
Alain Artola ◽  
Radhouane Dallel
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mechanical Allodynia ◽  
Molecular Mechanisms ◽  
Spontaneous Pain ◽  
Secondary Hyperalgesia ◽  
Neuronal Activation ◽  
Kinase C ◽  
C Fiber ◽  
Static Mechanical

Abstract Background Tissue injury enhances pain sensitivity both at the site of tissue damage and in surrounding uninjured skin (secondary hyperalgesia). Secondary hyperalgesia encompasses several pain symptoms including pain to innocuous punctate stimuli or static mechanical allodynia. How injury-induced barrage from C-fiber nociceptors produces secondary static mechanical allodynia has not been elucidated. Methods Combining behavioral, immunohistochemical, and Western blot analysis, the authors investigated the cell and molecular mechanisms underlying the secondary static mechanical allodynia in the rat medullary dorsal horn (MDH) using the capsaicin model (n = 4 to 5 per group). Results Intradermal injection of capsaicin (25 μg) into the vibrissa pad produces a spontaneous pain and a secondary static mechanical allodynia. This allodynia is associated with the activation of a neuronal network encompassing lamina I–outer lamina III, including interneurons expressing the γ isoform of protein kinase C (PKCγ) within inner lamina II (IIi) of MDH. PKCγ is concomitantly phosphorylated (+351.4 ± 79.2%, mean ± SD; P = 0.0003). Mechanical allodynia and innocuous punctate stimulus–evoked laminae I to III neuronal activation can be replicated after intracisternally applied γ-aminobutyric acid receptor type A (GABAA) antagonist (bicuculline: 0.05 μg) or reactive oxygen species (ROS) donor (tert-butyl hydroperoxide: 50 to 250 ng). Conversely, intracisternal PKCγ antagonist, GABAA receptor agonist, or ROS scavenger prevent capsaicin-induced static mechanical allodynia and neuronal activation. Conclusions Sensitization of lamina IIi PKCγ interneurons is required for the manifestation of secondary static mechanical allodynia but not for spontaneous pain. Such sensitization is driven by ROS and GABAAergic disinhibition. ROS released during intense C-fiber nociceptor activation might produce a GABAAergic disinhibition of PKCγ interneurons. Innocuous punctate inputs carried by Aδ low-threshold mechanoreceptors onto PKCγ interneurons can then gain access to the pain transmission circuitry of superficial MDH, producing pain.

Peripheral Analgesic Effects of Ketamine in Acute Inflammatory Pain 

1998 ◽  
Vol 89 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Juri L. Pedersen ◽  
Tina S. Galle ◽  
Henrik Kehlet
Keyword(s):  
Inflammatory Pain ◽  
Burn Injury ◽  
Systemic Treatment ◽  
Local Treatment ◽  
Human Model ◽  
Mechanical Stimuli ◽  
Pain Thresholds ◽  
Analgesic Effects ◽  
Relevant Effect ◽  
Double Blinded

Unlabelled BACKGROUND. This study examined the analgesic effect of local ketamine infiltration, compared with placebo and systemic ketamine, in a human model of inflammatory pain. Methods Inflammatory pain was induced by a burn (at 47 degrees C for 7 min; wound size, 2.5 x 5 cm) on the calf in 15 volunteers on 3 separate days with 7-day intervals. They received either (1) subcutaneous infiltration with ketamine in the burn area (local treatment) and contralateral placebo injections, or (2) subcutaneous ketamine contralateral to the burn (systemic treatment) and placebo in the burn area, or (3) placebo on both sides. The study was double-blinded and the order of the treatments was randomized. Hyperalgesia to mechanical and heat stimuli was examined by von Frey hairs and contact thermodes (3.75 and 12.5 cm2), and pain was rated using a visual analog scale (0-100). Results The burns produced significant hyperalgesia. Local ketamine infiltration reduced pain during the burn injury compared with systemic treatment and placebo (P &lt; 0.01). Heat pain thresholds were increased by local ketamine treatment compared with placebo immediately after injection (P &lt; 0.03), and so were the mechanical pain thresholds (P = 0.02). Secondary hyperalgesia and suprathreshold pain responses to heat and mechanical stimuli were not significantly affected by local ketamine. No difference between local ketamine and placebo could be detected 1 h and 2 h after the burn. Conclusions Ketamine infiltration had brief local analgesic effects, but several measures of pain and hyperalgesia were unaffected. Therefore, a clinically relevant effect of peripheral ketamine in acute pain seems unlikely.

scholarly journals The Analgesic Effects of Celecoxib on the Formalin-induced Short- and Long-term Inflammatory Pain

2017 ◽  
Vol 4 (20;4) ◽  
pp. E575-584 ◽  
Author(s):  
Ya-Qun Zhao
Keyword(s):  
Inflammatory Pain ◽  
Formalin Test ◽  
Formalin Injection ◽  
Spontaneous Pain ◽  
Second Phase ◽  
Secondary Hyperalgesia ◽  
Analgesic Effects ◽  
Gastrointestinal Side Effects ◽  
Short And Long Term

The non-steroidal anti-inflammatory drug celecoxib has long been used for reducing pain, in spite of moderate gastrointestinal side effects. In previous studies, it has been shown that celecoxib can inhibit formalin-induced spontaneous pain and secondary hyperalgesia. Injecting formalin into a rodent’s hind paw not only induces acute pain behaviors, but also produces long-lasting hyperalgesia. Whether celecoxib can also have long-lasting effects is still unknown. Our results show that pretreatment with an intraperitoneal injection of celecoxib at one hour before formalin injection induced inhibition on the spontaneous flinch and licking behaviors in the second phase but not the first phase. Meanwhile, FOS expressions were also reduced with celecoxib pretreatment. Consecutive administration of celecoxib also protects the hind paw from hypoalgesia and relieves formalininduced, long-lasting hyperalgesia in the ipsilateral hind paw. These analgesic effects may be related to suppression of the activation of neurons and astrocytes indicated by FOS and GFAP expressions. Based on the above findings, celecoxib demonstrated analgesic effects not only on acute spontaneous pain behavior but also on long-lasting hyperalgesia induced by formalin injection. The inhibition of neurons and astrocytes by celecoxib may be possible reasons for its analgesia. Key words: Formalin test, celecoxib, FOS, GFAP, hyperalgesia

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