Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia

BACKGROUND: The n-methyl-d-aspartate receptor antagonists such as ketamine relieve chronic pain but their oral and parenteral use is limited by the adverse effects. Experimental studies indicate that the peripheral n-methyl-d-aspartate receptors are involved in nociception. Recent clinical findings suggest that ketamine gel alleviates neuropathic pain, but no placebo-controlled randomized studies are available on the neurosensory effects of ketamine gel in experimental neurogenic pain. OBJECTIVES: The aim of this study was to assess the effects of topically applied ketamine using the intradermal capsaicin model in healthy volunteers. METHODS: Nine healthy subjects received ketamine and placebo gel on 3 occasions in a randomized, double-blind, and crossover manner. The concentration of ketamine was 50 mg/mL. One milliliter of gel was rubbed into the skin of both forearms 10 minutes before the intradermal injection of capsaicin (250 microg). Thereafter, the intensity and unpleasantness of spontaneous and evoked pain and dysesthesia was assessed up to 60 minutes using a 10-cm visual analog scale. Pain and dysesthesia were evoked using cotton gauze, a von Frey microfilament, and 38 degrees C, 42 degrees C, and 47 degrees C heat. Side effects were recorded, and individuals' subjective experiences were assessed with a standard questionnaire. RESULTS: Ketamine gel had no effect on immediate burning pain followed by the capsaicin injection. Both the intensity and unpleasantness of mechanical hyperalgesia was statistically significantly reduced by ketamine gel applied both on the left and right side. Neither tactile allodynia evoked by a brush nor thermal hyperalgesia were observed in any volunteer. No local or systemic side effects were observed. No patient reported any drug effects. DISCUSSION: A significant reduction of mechanical hyperalgesia was produced by topically and pre-emptively applied ketamine in healthy patients. We propose that the mechanism of action would be the reduction of central sensitization caused by the absorption of ketamine in circulation.     

No effect of sympathetic sudomotor activity on capsaicin-evoked ongoing pain and hyperalgesia

BACKGROUND: Complex regional pain syndromes (causalgia and RSD) can be relieved by blockade of the sympathetic efferent activity. The mechanisms of sympathetically maintained pain (SMP) are unclear. So far an adrenergic interaction between sympathetic vasoconstrictor neurons and nociceptors has been proposed. Alternatively, a cholinergic coupling of sympathetic sudomotor neurons and nociceptors is possible. OBJECTIVE: To determine the effect of cutaneous sympathetic sudomotor activity on pain induced by primary afferent C-nociceptor activation with capsaicin in humans. METHODS: In 10 healthy volunteers capsaicin was injected into the forearm skin to induce ongoing pain and dynamic and punctate mechanical hyperalgesia. Intensity of pain and hyperalgesia and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of low and high sympathetic sudomotor skin activity induced by whole-body temperature changes with a thermal suit. By altering whole-body temperature from a moderately warm to an intensely warm state, sympathetic sudomotor activity is modulated selectively in the widest range that can be achieved physiologically while sympathetic vasoconstrictor activity is continuously inhibited. The degree of sudomotor discharge was monitored by measuring cutaneous sweat production at the forearm with the colour indicator ponso-red. The inhibition of vasocontrictor discharge was monitored by measuring cutaneous blood flow at the index finger with laser Doppler flowmetry. RESULTS: The intensity and spatial distribution of capsaicin-evoked ongoing pain and dynamic and punctate mechanical hyperalgesia were not significantly different during the presence of high and low sympathetic sudomotor discharge. Conclusions: Cutaneous sympathetic sudomotor activity does not influence capsaicin induced pain and mechanical hyperalgesia.     

Intrathecal protease-activated receptor stimulation produces thermal hyperalgesia through spinal cyclooxygenase activity

Activation of protease-activated receptors (PARs) in non-neural tissue results in prostaglandin production. Because PARs are found in the spinal cord and increased prostaglandin release in the spinal cord causes thermal hyperalgesia, we hypothesized that activation of these spinal PARs would stimulate prostaglandin production and cause a cyclooxygenase-dependent thermal hyperalgesia. PARs were activated using either thrombin or peptide agonists derived from the four PAR subtypes, delivered to the lumbar spinal cord. Dialysis experiments were conducted in conscious, unrestrained rats using loop microdialysis probes placed in the lumbar intrathecal space. Intrathecal thrombin stimulated release of prostaglandin E (PGE)(2) but not aspartate or glutamate. Intrathecal delivery of the PAR 1-derived peptide SFLLRN-NH(2) and the PAR 2-derived peptide SLIGRL both stimulated PGE(2) release; PAR 3-derived TFRGAP and PAR 4-derived GYPGQV were inactive. Intrathecal thrombin had no effect upon formalin-induced flinching or tactile sensitivity but resulted in a thermal hyperalgesia. Intrathecal SFLLRN-NH(2) and SLIGRL both produced thermal hyperalgesia. Consistent with their effects on spinal PGE(2), hyperalgesia from these peptides was blocked by pretreatment with the cyclooxygenase inhibitor ibuprofen. SLIGRL-induced hyperalgesia was also blocked by the selective inhibitors SC 58,560 [5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole; cyclooxygenase (COX) 1] and SC 58,125 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; COX 2]. These data indicate that activation of spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal cyclooxygenase cascade and a prostaglandin-dependent thermal hyperalgesia.     

Electroacupuncture suppresses capsaicin-induced secondary hyperalgesia through an endogenous spinal opioid mechanism

Central sensitization, caused either by tissue inflammation or peripheral nerve injury, plays an important role in persistent pain. An animal model of capsaicin-induced pain has well-defined peripheral and central sensitization components, thus is useful for studying the analgesic effect on two separate components. The focus of this study is to examine the analgesic effects of electroacupuncture (EA) on capsaicin-induced secondary hyperalgesia, which represents central sensitization. Capsaicin (0.1%, 20 μl) was injected into the plantar side of the left hind paw, and foot withdrawal thresholds in response to von Frey stimuli (mechanical sensitivity) were determined for both primary and secondary hyperalgesia in rats. EA (2 Hz, 3 mA) was applied to various pairs of acupoints, GB30–GB34, BL40–BL60, GV2–GV6, LI3–LI6 and SI3–TE8, for 30 min under isoflurane anesthesia and then the effect of EA on mechanical sensitivity of paw was determined. EA applied to the ipsilateral SI3–TE8, but to none of the other acupoints, significantly reduced capsaicin-induced secondary hyperalgesia but not primary hyperalgesia. EA analgesic effect was inhibited by a systemic non-specific opioid receptor (OR) antagonist or an intrathecal μ- or δ-OR antagonist. EA analgesic effect was not affected by an intrathecal κ-OR antagonist or systemic adrenergic receptor antagonist. This study demonstrates that EA produces a stimulation point-specific analgesic effect on capsaicin-induced secondary hyperalgesia (central sensitization), mediated by activating endogenous spinal μ- and δ-opioid receptors.     

Substance P and peripheral inflammatory hyperalgesia

The hyperalgesic effect of substance P (SP) is usually described as presenting short latency. We now report that multiple injections of sub-threshold doses of SP into the foot pad of a hind paw of rats pre-treated with indomethacin induced a long-lasting hyperalgesia, sensitizing the paw to further challenges with small doses of SP, dopamine or prostacyclin. The sensitizing process also occurred after multiple injections of prostacyclin or prostaglandin E2. The sensitizing effect induced by SP, prostaglandin E2 or prostacyclin is inhibited by pre-treatment with the SP antagonist (D-Arg, D-Pro, D-Trp, Leu)-SP. We suggest that SP has an important role as a modulator in peripheral inflammatory pain by sensitizing nociceptors to its own action and to the action of different mediators. This sensitizing process could also be associated with chronic inflammatory pain.     

Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia

Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B2 agonists activate sensory neurones directly, B1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B1 receptors in inflammatory hyperalgesia. Therefore we have examined B1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia. In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B1 agonist, desArg9BK, did not affect paw withdrawal thresholds in nai;ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.     

Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia

High-threshold voltage-dependent calcium channels enable calcium ions to enter neurons upon depolarization and thereby influence synaptic mediator/receptor systems, membrane excitability levels, second and third messenger concentration, and gene expression. These phenomena underlie several processes including those of normal nociception and of hyperalgesia and allodynia. The present article deals with the role of spinal L-, N- and P/Q-type calcium channels in short-lasting nociception as well as in the hyperalgesia and allodynia elicited by chemical irritants of peripheral nociceptors, inflammatory and mechanical lesions of peripheral tissues, and lesions of peripheral nerves. The studies summarized herein are based on the spinal delivery of specific antagonists to high-threshold calcium channels, and reveal that blockade of L-type, P/Q-type and, particularly, N-type channels can prevent, attenuate, or both, subjective pain as well as primary and/or secondary hyperalgesia and allodynia in a variety of experimental and clinical conditions.     

Cannabinoids modulate pain by multiple mechanisms of action

Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects.     

Attenuation of capsaicin-evoked mechanical allodynia by peripheral neuropeptide Y Y1 receptors

Neuropeptide Y (NPY) and its cognate receptors are important modulators of nociception and their expression is significantly altered following injury. In particular, previous studies have demonstrated that the Y1 subtype of NPY receptors inhibits nociceptive transmission from capsaicin-sensitive terminals in the dorsal horn of the spinal cord. The present study evaluated the function of the Y1 receptor on peripheral terminals of primary afferent neurons by testing whether peripherally administered Y1 agonists and antagonists alter capsaicin-evoked mechanical allodynia in rats and capsaicin-evoked immunoreactive calcitonin gene-related peptide (iCGRP) release from isolated superfused rat skin. Treatment with the Y1 agonist [Leu31,Pro34]-NPY (0.5, 1, or 10 nmol) significantly inhibited capsaicin-evoked mechanical allodynia in a dose-dependent manner. This effect was reversible by pretreatment with the Y1 antagonist BIBO3304 (10 nmol). The anti-allodynia produced by the Y1 agonist occurred at a peripheral site of action, because injection into the paw contralateral to the site of the capsaicin injection had no effect on paw withdrawal latencies. In isolated skin, application of [Leu31,Pro34]-NPY (300 nM) significantly inhibited capsaicin-evoked CGRP release. BIBO3304 reversed this inhibition, having itself no effect on capsaicin-evoked iCGRP release. These studies indicate that the activation of peripheral Y1 receptors produces anti-allodynia, possibly via the direct inhibition of capsaicin-sensitive fibers.     

Cerebral mechanisms of experimental hyperalgesia in fibromyalgia

The present study examined the hyperresponsiveness of the central nervous system in patients with fibromyalgia syndrome (FMS) related to mechanical hyperalgesia. The goals were to differentiate between increased pain ratings and hyperalgesia related either to peripheral or to central sensitization and to correlate with cerebral activation pattern. Seventeen patients and 17 healthy controls were examined, placing an experimental incision in the right volar forearm and causing tonic pain. Experimental pain, primary and secondary hyperalgesia were assessed during the time course of the experimental pain, and the changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Patients with FMS experienced the experimental pain during the time course as more painful than healthy controls (F_score = 3.93, p_score = 0.008). While they did not present a different course of primary hyperalgesia (F_score = 1.01, p_score = 0.40), they did show greater secondary hyperalgesia (F_score = 5.45, p_score = 0.004). In patients with FMS, the cerebral pattern corresponding to secondary hyperalgesia was altered. The activity in the dorsolateral prefrontal cortex was inversely correlated with secondary hyperalgesia in healthy controls (R = ?0.34 p = 0.005); in patients, this correlation was disrupted (R = 0.19 p = 0.12). These findings point to an alteration of pain transmission at the central level in FMS (e.g., loss of inhibition) and might be related to changes in cerebral‐midbrain‐spinal mechanisms of pain inhibition.     

Activation of peripheral ephrinBs/EphBs signaling induces hyperalgesia through a MAPKs-mediated mechanism in mice

EphBs receptors and ephrinBs ligands are present in the adult brain and peripheral tissue and play a critical role in modulating multiple aspects of physiology and pathophysiology. Ours and other studies have demonstrated that spinal ephrinBs/EphBs signaling was involved in the modulation of nociceptive information and central sensitization. However, the role of ephrinBs/EphBs signaling in peripheral sensitization is poorly understood. This study shows that intraplantar (i.pl.) injection of ephrinB1-Fc produces a dose- and time-dependent thermal and mechanical hyperalgesia and the increase of spinal Fos protein expression in mice, which can be partially prevented by pre-treatment with EphB1-Fc. EphrinB1-Fc-induced hyperalgesia is accompanied with the NMDA receptor-mediated increase of expression in peripheral and spinal phosphorylated mitogen-activated protein kinases (phospho-MAPKs) including p-p38, pERK and pJNK, and also is prevented or reversed by the inhibition of peripheral and spinal MAPKs. Furthermore, in formalin inflammation pain model, pre-inhibition of EphBs receptors by the injection of EphB1-Fc reduces pain behavior, which is accompanied by the decreased expression of peripheral p-p38, pERK and pJNK. These data provide evidence that ephrinBs may act as a prominent contributor to peripheral sensitization, and demonstrate that activation of peripheral ephrinBs/EphBs system induces hyperalgesia through a MAPKs-mediated mechanism.     

Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations

Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.     

Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia

The neuromodulatory interactions of sex steroids with the opioid system may result in sex differences in pain and analgesia. Dynorphin is an endogenous kappa-opioid peptide that is upregulated in an animal model of peripheral inflammation and hyperalgesia and is possibly regulated by circulating levels of sex steroids. The present study compared behavioral responses of male, cycling female, and gonadectomized Sprague-Dawley rats in a model of persistent pain. Cycling female rats were behaviorally tested over a 14-day period, and their estrous cycles were monitored by daily vaginal smears. Thermal hyperalgesia was measured by paw withdrawal latencies taken prior to and 24-72 h after rats received a unilateral hindpaw injection of complete Freund's adjuvant (CFA). Prior to CFA administration, there was no significant difference in paw withdrawal latencies between male rats, cycling female rats, and ovariectomized female rats. Following CFA administration, female rats in proestrus exhibited significantly increased hyperalgesia compared with male rats, ovariectomized female rats, and female rats in other estrous stages (P相似文献   

Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitisation

Ultraviolet (UV) induced cutaneous inflammation is emerging as a model of pain with a novel sensory phenotype. A UVB dose of 1000 mJ/cm2 produces a highly significant thermal and mechanical hypersensitivity. Here we examined the properties and mechanisms of such hyperalgesia in rats. Significantly, the mechanical hyperalgesia (with ∼60% change in withdrawal thresholds) was restricted to the lesion site with no changes in mechanical threshold in adjacent non-irradiated skin (i.e. no secondary hypersensitivity), suggesting a peripheral mechanism. Consistent with this, we found that primary mechanical hypersensitivity showed no significant changes after intrathecal treatment with 10 μg of the NMDA-receptor antagonist MK-801. Using an in vitro skin–nerve preparation, in the presence and absence of UVB-inflammation, suprathreshold responses to skin displacement stimuli of 6–768 μm of 103 peripheral nociceptors were recorded. At the peak of UVB-induced hyperalgesia we observed that mechanical response properties of Aδ-nociceptors recorded from UVB-inflamed skin (n = 19) were significantly diminished, by ∼50%, compared to those recorded from naïve skin (n = 13). The mechanical response properties of heat-sensitive C-nociceptors were unchanged while their heat responses were significantly increased, by ∼75%, in UVB-inflamed (n = 26) compared to naïve skin (n = 12). Heat-insensitive C-nociceptors, however, demonstrated significantly enhanced (by ∼60%) response properties to mechanical stimulation in UVB-inflamed (n = 21) compared to naïve skin (n = 12). Notably alteration in mechanical responses of Aδ- and heat-insensitive C-nociceptors were particular to stronger stimuli. Spontaneous activity was not induced by this dose of UVB. We conclude that UVB-induced mechanical hyperalgesia may be explained by a net shift in peripheral nociceptor response properties.     

Noradrenergic mechanisms in mediation of stress-induced hyperalgesia in rats

Exposure to a mild stressor (15 min of vibration) produced analgesia in some rats and hyperalgesia in other rats from the same batch treated in the same way. Rats which responded with decreased tail-flick latencies (TFL) showed signs of hyperemotionality during the stress procedure. Stress-induced hyperalgesia was abolished by the administration of diazepam (2.5 mg/kg i.p.) and clonidine (25 micrograms/kg i.p.). It is suggested that the reversal of hyperalgesia was due to the anxiolytic properties of the drugs. Yohimbine, an alpha 2-adrenoceptor antagonist (5 mg/kg i.p.), antagonized the effect of clonidine. The influence of clonidine on stress-induced hyperalgesia may be mediated by alpha 2-adrenoceptors.     

The effect of spinal and systemic administration of indomethacin on zymosan-induced edema, mechanical hyperalgesia, and thermal hyperalgesia.

Pretreatment with intraperitoneal (i.p.) indomethacin was used to determine whether indomethacin preferentially affected the development of edema and hyperalgesia to thermal and mechanical stimuli produced by injection of zymosan in the ispsilateral hindpaw of the rat. Indomethacin also was delivered intrathecally (i.t.) either 30 minutes before or 4 hours after intraplantar zymosan to determine whether spinal prostaglandin production was important for the induction and/or maintenance of hyperalgesia. Zymosan alone produced a robust edema, a monophasic mechanical hyperalgesia, and a biphasic thermal hyperalgesia in the ipsilateral hindpaw. Systemic administration of indomethacin reduced zymosan-induced edema and increased thermal and mechanical response thresholds in the zymosan-injected paw. Systemic indomethacin did not affect thermal withdrawal response thresholds in the uninjected contralateral hindpaw of zymosan-treated rats, but significantly increased mechanical withdrawal thresholds of the uninjected contralateral paw of zymosan-treated rats. i.t. administration of indomethacin before the induction of hyperalgesia attenuated the development of zymosan-induced mechanical hyperalgesia, but did not affect the development of either zymosan-induced edema or thermal hyperalgesia. Once hyperalgesia was established, i.t. indomethacin also attenuated the mechanical hyperalgesia whereas it had no effect on thermal hyperalgesia or edema. These data suggest that peripheral, but not spinal prostaglandins contribute to the edema and development of thermal hyperalgesia produced by zymosan. In contrast, spinal prostaglandins contribute to the development and maintenance of mechanical hyperalgesia.     

Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain

Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.