kallidin and Pain

Kinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; Bradykinin; Cardiovascular Physiological Phenomena; Humans; Inflammation; Kallidin; Kinins; Models, Biological; Molecular Sequence Data; Nervous System Physiological Phenomena; Pain; Rats; Receptors, Bradykinin; Vasomotor System; Wounds and Injuries

To determine the muscular concentration of bradykinin and kallidin during static contraction, microdialysis probes were implanted bilaterally in the trapezius muscles of healthy women. Three hours after probe implantation, 200 microM of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat were added to the perfusion solution in one of the sides for 30 min. Thirty minutes later, the subjects performed a sustained bilateral shoulder abduction at 10% of the maximal voluntary contraction until exhaustion. This protocol was repeated twice, with an interval of at least 17 days. High intersession repeatability was observed in the concentration of bradykinin but not of kallidin. Enalaprilat induced a significant increase in bradykinin levels in the dialysate, without affecting kallidin levels. The sustained contraction induced a significant increase in dialysate levels of both kinin peptides. The contraction also induced a significant increase in pain ratings, as measured by a visual analog scale. During contraction, positive correlations were found between pain ratings and levels of kinin peptides in dialysate, predominantly in the side previously perfused with enalaprilat. Subjects with the higher pain ratings also showed larger increases in kinin peptides in the side previously perfused with enalaprilat. The present results show that both plasma and tissue kinin-kallikrein are activated during muscle contraction, but that their metabolic pathways are differently regulated during rest and contraction, because they showed a different response to ACE inhibition. They also indicate that intramuscular kinin peptides levels, and ACE activity, may contribute to muscle pain.

Topics: Adult; Bradykinin; Female; Humans; Isometric Contraction; Kallidin; Kinins; Microdialysis; Muscle, Skeletal; Neuropeptides; Pain; Physical Endurance; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index; Shoulder; Statistics as Topic

1. Kallidin (5-500 nmol), hypertonic saline (0.9-20% NaCl) or low pH medium (citric acid: pH 2.5-1) applied (50 microliters) to the human nasal mucosa produced a pain response (evaluated by a visual analogue scale) that was related to the concentration of the peptide, NaCl or hydrogen ions, respectively. 2. Application (50 microliters) of capsaicin (50 nmol) to the human nasal mucosa produced overt pain. After repeated administrations (once a day for 5-7 days) to one nostril this effect underwent almost complete desensitization, while in the contralateral nostril, treated with the vehicle, the response to capsaicin was unaffected. 3. The pain response produced in the human nasal mucosa by topical application (50 microliters) or kallidin (50-500 nmol), NaCl (10-20%) or citric acid (pH 1.5-1) solutions was then studied before and after local capsaicin desensitization. 4. The pain response to pH 1.5 or 1 citric acid was markedly reduced (by 60% and 75%, respectively) in the capsaicin-treated nostril. However, the pain response to 10% or 20% NaCl or the mild pain response to 50 or 500 nmol kallidin were unaffected by capsaicin pre-treatment. 5. The present results suggest that prolonged topical capsaicin treatment to the human nasal mucosa may lead to selective desensitization to certain algesic stimuli such as capsaicin itself and hydrogen ions.

Topics: Administration, Intranasal; Adolescent; Adult; Analysis of Variance; Capsaicin; Citrates; Citric Acid; Female; Humans; Hydrogen-Ion Concentration; Kallidin; Male; Middle Aged; Nasal Mucosa; Pain; Saline Solution, Hypertonic

The origins of chronic muscle pain development and maintenance are debated regarding the relative contributions of peripheral nociception and central pain processing. Bradykinin (BKN) and kallidin (KAL) have been suggested to be algesic kinins involved in muscle pain. This in vivo study investigates whether there were significant differences in interstitial muscle concentrations of BKN and KAL between chronic work-related trapezius myalgia (TM), chronic whiplash associated disorders (WAD), and healthy controls (CON). These subjects were studied at rest, during a 20-min repetitive low-force exercise and recovery. The interstitial concentrations of BKN and KAL of trapezius were determined using the microdialysis technique. The interstitial concentration of KAL was overall significantly higher in TM than in CON. [KAL] and [BKN] increased significantly during the brief exercise in all groups. The increase in [BKN] during exercise was significantly higher in TM than in the other two groups, whereas the increase in [KAL] during exercise was highest in WAD. In chronic pain, positive correlations existed between the two kinins and the difference in pain intensity between recovery and baseline. In this in vivo study of two groups of patients with chronic pain clinically involving the trapezius muscle, we found alterations - most prominent in TM - in the interstitial concentrations of BKN and KAL. The results indicated that the two kinins were involved in aspects of hyperalgesia.

Topics: Adult; Blood Flow Velocity; Bradykinin; Cumulative Trauma Disorders; Exercise Test; Female; Humans; Kallidin; Microdialysis; Middle Aged; Muscle, Skeletal; Muscular Diseases; Occupational Diseases; Pain; Pain Measurement; Pain Threshold; Pressure; Whiplash Injuries; Young Adult

An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hours after CFA injection, whereas a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hours. Thermal hyperalgesia at day 3, but not at 6 hours, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin on peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia.. This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.

Topics: Adjuvants, Immunologic; Analysis of Variance; Animals; Bradykinin; Dynorphins; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Spinal; Kallidin; Kininogens; Male; Pain; Pain Measurement; Pain Threshold; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Tritium; Up-Regulation

The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500-700 g), baseline hind paw withdrawal thresholds typically fell within the 60-80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 microL, intra-plantar), withdrawal thresholds dropped by approximately 30-40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED50=2.56 mg/kg, p.o.) or the bradykinin B2 receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED50=0.096 mg/kg, s.c.) or the bradykinin B1 receptor peptide antagonist [des-Arg10, Leu9]-kallidin (ED50=0.45 mg/kg, s.c.). Rabbits treated with the novel B(1) receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED50=20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic-pharmacodynamic (PK-PD) relationships (compound A plasma EC50=402.6 nM). We conclude that the Electrovonfrey method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Dose-Response Relationship, Drug; Drug Interactions; Ethers; Hydrocarbons, Fluorinated; Hyperalgesia; Indomethacin; Inflammation; Kallidin; Metacarpus; Pain; Pain Measurement; Pain Threshold; Rabbits; Reaction Time; Spectrum Analysis; Time Factors

Bradykinin B1 and B2 receptors contribute to nociceptor sensitization under inflammatory conditions. Here, we examined the vascular inflammatory responses and nociceptive effects resulting from activation of B1 and B2 receptors in healthy and UV-B irradiated skin in human volunteers. The B1 receptor agonist des-Arg(10)-Kallidin (10(-6)-10(-3)M) and the B2 receptor agonist bradykinin (10(-9)-10(-4)M) were administered by dermal microdialysis to the ventral thigh. UV-B irradiation was performed 24 h prior to the experiment with the threefold minimum erythemal dose. Pain sensation perceived during the stimulation with the bradykinin receptor agonists was estimated on a numeric scale. Local and axon reflex-induced vasodilations were recorded by laser Doppler imaging. For protein extravasation, total protein content in the dialysate was assessed as a measure of increased endothelial permeability. In normal skin, both B1 and B2 receptor activation dose-dependently evoked pain, vasodilatation and protein extravasation. In UV-B irradiated skin, pain sensation and axon reflex vasodilatation were enhanced by both B1 and B2 agonists, whereas local vasodilatation was increased only following B1 receptor activation. The UV-B irradiation did not enhance B1 and B2 receptor-induced protein extravasation indicating a differential sensitization of the neuronal, but not the vascular response.

Topics: Adult; Analysis of Variance; Bradykinin; Dose-Response Relationship, Drug; Erythema; Female; Humans; Kallidin; Laser-Doppler Flowmetry; Male; Microdialysis; Pain; Pain Measurement; Proteins; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Regional Blood Flow; Skin; Time Factors; Ultraviolet Rays

This study investigates the effect and some of the mechanisms involved following systemic treatment of mice with Mycobacterium bovis bacillus Calmette-Guérin (BCG) (1 dose per animal containing 6.4 x 10(4) colony-forming units (CFu) 20-60 days beforehand) on modulation of the kinin B1 receptor agonist-induced nociception and oedema formation in the formalin test. Intraplantar (i.p.l.) co-injection of des-Arg9-bradykinin (4-32 nmol/paw) or des-Arg10-kallidin (1-15 nmol/paw), together with sub-maximal concentrations of formalin (0.01 or 0.5%), potentiated (P < 0.01) both pain phases and the paw oedema caused by formalin in animals pre-treated with saline. However, when animals were pre-treated with BCG, the dose-response curves for both B1 agonists were shifted 2 to 8-fold to the left. These B1-mediated effects peaked at 30-45 days after BCG treatment and were still elevated at 60 days after BCG injection. The pain response and oedema formation caused by i.p.l. co-injection of des-Arg9-bradykinin, together with formalin in BCG-pre-treated animals, were dose-dependently antagonised by i.p.l. co-injection of the B1 antagonist des-Arg9[Leu8]bradykinin (1-15 nmol/paw), but were not affected by the B2 antagonist Hoe 140 (10 nmol/paw). The i.p.l. co-injection of tyrosine8-bradykinin (a B2 agonist, 3-15 nmol/paw) with formalin (0.01 or 0.5%) potentiated the pain response and paw oedema in BCG and saline-pre-treated animals to the same extent (P < 0.01). The actions caused by tyrosine8-bradykinin were antagonised by Hoe 140, while des- Arg9[Leu8]bradykinin (10 nmol/paw) had no effect. Dexamethasone (0.5 mg/kg, s.c.), given every 24 h, from day 0 to 30-45, inhibited significantly the potentiation of nociceptive response and oedema formation caused by i.p.l. co-injection of formalin plus des-Arg9-bradykinin, while indomethacin (2 mg/kg, i.p.) or phenidone (30 mg/kg, i.p.), given 1 h prior, caused less inhibition. These data show that the long-term systemic treatment of mice with BCG produced dose-related potentiation of B1 receptor agonist-mediated nociception and oedema formation, without affecting similar responses caused by the B2 receptor agonist tyrosine8-bradykinin. Thus, systemic treatment of mice with BCG induces upregulation of B1 receptors, without affecting B2-mediated responses, by a mechanism that seems to be secondary to cytokine release.

Topics: Animals; Bradykinin; Dexamethasone; Dose-Response Relationship, Drug; Drug Synergism; Edema; Formaldehyde; Hindlimb; Indomethacin; Kallidin; Male; Mice; Mycobacterium bovis; Pain; Pain Measurement; Pyrazoles; Receptor, Bradykinin B1; Receptors, Bradykinin

Various kinins (dissolved in 50 microliters) were applied to the nasal mucosa of healthy human volunteers to test the algesic and proinflammatory effects of these peptides in an intact human tissue. [des-Arg9]-bradykinin (0.5 mumol) was found to be inactive, while bradykinin (0.05-0.5 mumol) and especially kallidin (0.005-0.5 mumol) induced: (a) a mild painful sensation described as burning and pricking (latency 30 s, duration 3-5 min), (b) perception of pulsatility and obstruction in the nasal cavity (onset 1 min, duration 6-8 min). Substance P (0.5 mumol) and neurokinin A (0.5 mumol) produced slight obstruction and weak pulsatile sensation but not pain. Capsaicin (0.05 nmol) produced pain and secretion of fluid, but not pulsatile sensation. The effects of kallidin were not affected by repeated (to induce desensitization) applications of capsaicin (0.5 mumol). Likewise, ipratropium bromide (80 mg in 100 microliters) did not affect responses to kallidin. In an intact human tissue, kallidin produces various effects, including an algesic response, that are apparently independent from activation of B1 receptors and from desensitization of capsaicin-sensitive primary afferents.

Topics: Adult; Capsaicin; Female; Humans; Ipratropium; Kallidin; Kinins; Male; Nasal Mucosa; Pain; Tachykinins

Topics: Analgesics; Angiotensin II; Bradykinin; Humans; Kallidin; Kinins; Pain; Peptides; Substance P

Topics: Adult; Bradykinin; Eledoisin; Female; Humans; Kallidin; Male; Pain

Topics: Bradykinin; Drug Tolerance; Humans; Injections; Injections, Intravenous; Kallidin; Male; Neurophysiology; Nociceptors; Pain; Peptides; Sensory Receptor Cells; Serotonin; Tachyphylaxis

Topics: Bradykinin; Capillaries; Embolism; Fibrinolysis; Humans; Kallidin; Kinins; Pain; Peptides; Serotonin; Thrombosis

Nine behavioural responses were observed to follow with reasonable frequency intradermal injection into guinea-pigs of strongly anisotonic solutions, which are known to cause pain in human skin. These responses were recorded on a form, and a procedure was devised for obtaining a nociceptive score from the records. Intradermal injection of bradykinin or kallidin-10 gave a response pattern indistinguishable from that to a strongly anisotonic solution. Each kinin raised the nociceptive score in response to the control solutions, as also did acetylcholine and histamine; but 5-hydroxytryptamine and pH changes within the range of 3.1 to 10.3 did not significantly raise the control score. The effect of bradykinin was depressed by subcutaneous injection of morphine or codeine, but was unaffected by amidopyrine, calcium acetylsalicylate, chlorpromazine or phenylbutazone.

Topics: Acetylcholine; Animals; Bradykinin; Guinea Pigs; Histamine; Humans; Injections, Intradermal; Injections, Subcutaneous; Kallidin; Morphine; Pain; Peptides; Pharmacology; Physiology; Research; Serotonin