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PubMed1995

Involvement of the sympathetic postganglionic neuron in capsaicin-induced secondary hyperalgesia in the rat.

The involvement of the sympathetic postganglionic neuron in secondary hyperalgesia was evaluated using a model of secondary hyperalgesia induced by a small intradermal injection of capsaicin in the rat, a procedure known to produce mechanical hyperalgesia/allodynia in humans. Capsaicin injection into the glabrous skin of the hind paw led to increased sensitivity to mechanical stimulation with von Frey filaments at the injection site (i.e. primary hyperalgesia) as well as in an area of the hind paw remote from the site of injection (i.e. secondary hyperalgesia). Surgical removal of the sympathetic postganglionic neurons innervating the hind paw plantar skin before the capsaicin injection prevented secondary hyperalgesia. However, decentralization of the sympathetic postganglionic neurons subserving the hind paw did not effect secondary hyperalgesia. Phentolamine, an alpha-adrenergic receptor antagonist, as well as prazosin, an alpha 1-adrenergic receptor antagonist, given systemically, both blocked the development of secondary hyperalgesia. Yohimbine, an alpha 2-adrenergic receptor antagonist, was without effect. Prazosin also blocked the development of secondary hyperalgesia when given intradermally at the site of capsaicin injection. Activation of C-fibres with capsaicin induces secondary hyperalgesia, which is sympathetic postganglionic neuron-dependent. This sensory-sympathetic interaction is, however, independent of preganglionic sympathetic outflow and seems to be mediated by an alpha 1-adrenergic mechanism. Sensory-sympathetic interaction appears to take place in the area of capsaicin-induced C-fibre nociceptor activation.

Animals↗
PubMed1995

Kappa opioid receptors participate in nerve growth factor-induced hyperalgesia.

It has recently been observed that nerve growth factors induces the rapid onset of thermal hyperalgesia, and the more delayed onset of mechanical hyperalgesia when administered to mature rats. Though several mechanisms have been proposed to explain this phenomenon, it is still not well understood. Previous studies have shown that nerve growth factor can directly excite nociceptive sensory ganglion neurons in culture via activation of kappa excitatory opioid receptors. The possible involvement of these excitatory opioid receptors in mediating the hyperalgesia was investigated. Nerve growth factor-induced thermal hyperalgesia in rodents was prevented by co-administration of the non-selective opiate antagonist naloxone, as well as by the kappa-selective antagonist nor-binaltorphimine. Addition of the long-acting opioid antagonist, naltrexone, partially prevented mechanical hyperalgesia. Administration of low dose dynorphin to mice (a selective kappa-receptor agonist) mimicked the hyperalgesia effects of nerve growth factor. Opiate antagonists and anti-nerve growth factor antibody both interfered with Freund's adjuvant-induced inflammatory hyperalgesia. Altogether, these observations suggest that activation of excitatory opioid receptors plays a role in mediating nerve growth factor-induced hyperalgesia and that, in turn, nerve growth factor contributes to the hyperalgesia associated with inflammatory states. Since opioid receptor antagonists are well tolerated clinically, they may be useful for patients receiving nerve growth factor as part of ongoing trials of the factor in peripheral neuropathy.

Animals↗
PubMed2005

Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study.

Complex Regional Pain Syndromes (CRPS) are characterized by a triad of sensory, motor and autonomic dysfunctions of still unknown origin. Pain and mechanical hyperalgesia are hallmarks of CRPS. There are several lines of evidence that central nervous system (CNS) changes are crucial for the development and maintenance of mechanical hyperalgesia. However, little is known about the cortical structures associated with the processing of hyperalgesia in pain patients. This study describes the use of functional magnetic resonance imaging (fMRI) to delineate brain activations during pin-prick hyperalgesia in CRPS. Twelve patients, in whom previous quantitative sensory testing revealed the presence of hyperalgesia to punctuate mechanical stimuli (i.e. pin-prick hyperalgesia), were included in the study. Pin-prick-hyperalgesia was elicited by von-Frey filaments at the affected limb. For control, the identical stimulation was performed on the unaffected limb. fMRI was used to explore the corresponding cortical activations. Mechanical stimulation at the unaffected limb was non-painful and mainly led to an activation of the contralateral primary somatosensory cortex (S1), insula and bilateral secondary somatosensory cortices (S2). The stimulation of the affected limb was painful (mechanical hyperalgesia) and led to a significantly increased activation of the S1 cortex (contralateral), S2 (bilateral), insula (bilateral), associative-somatosensory cortices (contralateral), frontal cortices and parts of the anterior cingulate cortex. The results of our study indicate a complex cortical network activated during pin-prick hyperalgesia in CRPS. The underlying neuronal matrix comprises areas not only involved in nociceptive, but also in cognitive and motor processing.

Adult↗
PubMed2000

Carrageenan-induced thermal hyperalgesia in the mouse: role of nerve growth factor and the mitogen-activated protein kinase pathway.

NGF is an important link between inflammation and hyperalgesia and interacts with many different mediators of inflammation, including the MAPK signaling pathway. In these studies, carrageenan-induced thermal hyperalgesia was evaluated in the mouse and the role of NGF and the MAPK pathway investigated. Carrageenan induced a time-dependent inflammation and thermal hyperalgesia, which was maximal 4 h post administration. Both indomethacin (0.3, 1.0 and 10 mg/kg s.c., 30 min pre-carrageenan) and morphine (0.4, 1.2, 4.0 mg/kg; s.c., 30 min pre-hyperalgesia measurement) significantly inhibited carrageenan-induced thermal hyperalgesia and indomethicin inhibited paw inflammation, demonstrating the model as suitable for the assessment of anti-hyperalgesic and anti-inflammatory agents. Anti-NGF (0.67 mg/kg sc, 60 min pre-carrageenan) produced a significant inhibition of thermal hyperalgesia, but not inflammation. NGF itself produced a time-dependent hyperalgesia, but not inflammation, following intraplantar injection. The specific MAPK pathway inhibitor, PD98059 (0.1, 0.3 and 1 mg/kg sc, 30 min pre-carrageenan) significantly inhibited carrageenan-induced hyperalgesia, but not inflammation. These data demonstrate a role for both NGF and the MAPK signaling pathway in the production of thermal hyperalgesia, but not inflammation, in the mouse.

Analgesics, Opioid↗
PubMed2003

SYM 2081, an agonist that desensitizes kainate receptors, attenuates capsaicin and inflammatory hyperalgesia.

Excitatory amino acids acting at non-NMDA receptors contribute to transmission of nociceptive information. SYM 2081 ((2S,4R)-4-methyl glutamic acid) desensitizes kainate receptors, one subtype of non-NMDA receptors, to subsequent release of excitatory amino acids and thus may attenuate transmission of nociceptive information. To determine if SYM 2081 can prevent development of hyperalgesia, SYM 2081 (10, 50 or 100 mg/kg, i.p.) was administered prior to injection of capsaicin into the hindpaw of rats, which produces mechanical and heat hyperalgesia. To determine if SYM 2081 can reduce ongoing inflammatory hyperalgesia, SYM 2081 (10 or 100 mg/kg, i.p.) was administered after development of carrageenan-evoked hyperalgesia. Intraplantar injection of capsaicin produced an increase in hindpaw withdrawal frequency to mechanical stimuli (from 4+/-2 to 41+/-7%; mean+/-S.E.M.) and a decrease in withdrawal latency to heat (from 12.3+/-0.3 to 5.9+/-0.4 s) in rats that received vehicle. In contrast, rats that received SYM 2081 (100 mg/kg) prior to injection of capsaicin exhibited a lower hindpaw withdrawal frequency (18+/-4%) and a longer withdrawal latency (7.7+/-0.5 s). Intrathecal (1-100 microg/5 microl), but not intraplantar (10 or 100 microg/50 microl), injection of SYM 2081 attenuated the development of capsaicin-evoked heat hyperalgesia suggesting that SYM 2081's antihyperalgesic effects were due to its central effects. Furthermore, SYM 2081 completely reversed ongoing carrageenan-evoked mechanical hyperalgesia and partially (approximately 50%) reversed ongoing heat hyperalgesia. The present study demonstrates that administration of a high-potency ligand that selectively desensitizes kainate receptors attenuates the development of mechanical and heat hyperalgesia and attenuates ongoing inflammatory hyperalgesia.

Animals↗
PubMed2000

Contralateral heat hyperalgesia induced by unilaterally intraplantar bee venom injection is produced by central changes: a behavioral study in the conscious rat.

In a previous study, we found that subcutaneous (s.c.) intraplantar injection of bee venom unilaterally could produce bilateral heat hyperalgesia. However, the bee venom-induced heat hyperalgesia identified in the injection site was presumed to be different from that identified in the contralateral hindpaw, since the former co-existed with the mechanical hyperalgesia while the latter did not. The aim of the present study was to testify whether the contralateral heat hyperalgesia identified in the bee venom model was a consequence of central changes. The radiant heat and von Frey-type filaments were applied to both the injection site and the contralateral pawpad of conscious rats prior to and 4 h after s.c. bee venom injection. After confirmation of the development of primary heat and mechanical hyperalgesia and contralateral heat hyperalgesia following s.c. bee venom, the sciatic nerve of the injection side was transected. After axotomy, the bee venom-induced heat hyperalgesia in the non-injected hindpaw was not altered at all compared with that prior to axotomy. Moreover, intrathecal pre-treatment with either N-methyl-D-aspartate (NMDA) or non-NMDA receptor antagonist could prevent the development of the contralateral heat hyperalgesia. The present results suggest that central sensitization contributes to development of the bee venom-induced contralateral heat hyperalgesia and activation of both NMDA and non-NMDA receptors in the spinal cord is involved in the processing.

Animals↗
PubMed2003

The mu-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans.

Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to noxious stimuli often present in clinical pain, are important tools for studying antinociceptive drug profiles. The correct interpretation of results obtained in these models necessitates their mechanistic understanding. This study evaluated the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve healthy subjects were tested with mechanical (brush, punctuated and blunt) and electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after freezing the skin, and during a computer-controlled infusion of the mu-opioid agonist remifentanil targeting five different plasma concentrations between 0 and 6 ng/ml in a two-staged, single occasion, randomized, and double blind study design. Pharmacodynamic modeling techniques were used to describe the effect of freezing and drug administration on the mechanical and electrical pain thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to brushing or electrical stimuli was not detected. Remifentanil attenuated hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to punctuated stimuli, as indicated by a significantly steeper linear relationship between the remifentanil plasma concentration and the increase of the pain threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater potency for low frequency stimulation. The potency difference of remifentanil suggests that different neuronal mechanisms mediate hyperalgesia to blunt and punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is compatible with the view that mechanical hyperalgesia to blunt and punctuated stimulation of the freeze lesion is predominantly caused by a peripheral mechanism.

Adolescent↗
PubMed2003

A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain.

Pain associated with cancer and chronic musculoskeletal disorders can be difficult to control. We used murine models of cancer and inflammatory muscle pain to examine whether the cannabinoid receptor agonist WIN55,212-2 reduces hyperalgesia originating in deep tissues. C3H/He mice were anesthetized and implanted with osteolytic NCTC clone 2472 cells into the humeri or injected with 4% carrageenan into the triceps muscles of both forelimbs. At the time of peak hyperalgesia, WIN55,212-2 (1-30mg/kg) or vehicle was administered intraperitoneally and forelimb grip force was measured 0.5-24h later. WIN55,212-2 produced time- and dose-related antihyperalgesia in both models. A 10mg/kg dose of WIN55,212-2 fully reversed carrageenan-evoked muscle hyperalgesia. However, 30mg/kg of WIN55,212-2 attenuated tumor-evoked hyperalgesia only approximately 50%. After controlling for the difference in magnitude of hyperalgesia between the two models, WIN55,212-2 was still more potent at reducing hyperalgesia in the inflammatory model. In the cancer pain model, the antihyperalgesic effect of WIN55,212-2 was partially blocked by pretreatment with the selective CB1 (SR141716A) but not the CB2 (SR144528) receptor antagonist. In contrast, both antagonists blocked antihyperalgesic effects of WIN55,212-2 on carrageenan-evoked muscle hyperalgesia. Catalepsy and loss of motor coordination, known side effects of cannabinoids, did not account for the antihyperalgesia produced by WIN55,212-2. These data show that cannabinoids attenuate deep tissue hyperalgesia produced by both cancer and inflammatory conditions. Interestingly, cannabinoids differentially modulated carrageenan- and tumor-evoked hyperalgesia in terms of potency and receptor subtypes involved suggesting that differences in underlying mechanisms may exist between these two models of deep tissue pain.

Animals↗
PubMed2003

Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1.

Clinically, chronic pain and hyperalgesia induced by muscle injury are disabling and difficult to treat. Cellular and molecular mechanisms underlying chronic muscle-induced hyperalgesia are not well understood. For this reason, we developed an animal model where repeated injections of acidic saline into one gastrocnemius muscle produce bilateral, long-lasting mechanical hypersensitivity of the paw (i.e. hyperalgesia) without associated tissue damage. Since acid sensing ion channels (ASICs) are found on primary afferent fibers and respond to decreases in pH, we tested the hypothesis that ASICs on primary afferent fibers innervating muscle are critical to development of hyperalgesia and central sensitization in response to repeated intramuscular acid. Dorsal root ganglion neurons innervating muscle express ASIC3 and respond to acidic pH with fast, transient inward and sustained currents that resemble those of ASICs. Mechanical hyperalgesia produced by repeated intramuscular acid injections is prevented by prior treatment of the muscle with the non-selective ASIC antagonist, amiloride, suggesting ASICs might be involved. ASIC3 knockouts do not develop mechanical hyperalgesia to repeated intramuscular acid injection when compared to wildtype littermates. In contrast, ASIC1 knockouts develop hyperalgesia similar to their wildtype littermates. Extracellular recordings of spinal wide dynamic range (WDR) neurons from wildtype mice show an expansion of the receptive field to include the contralateral paw, an increased response to von Frey filaments applied to the paw both ipsilaterally and contralaterally, and increased response to noxious pinch contralaterally after the second intramuscular acid injection. These changes in WDR neurons do not occur in ASIC3 knockouts. Thus, activation of ASIC3s on muscle afferents is required for development of mechanical hyperalgesia and central sensitization that normally occurs in response to repeated intramuscular acid. Therefore, interfering with ASIC3 might be of benefit in treatment or prevention of chronic hyperalgesia.

Acid Sensing Ion Channels↗
PubMed1999

Nitroprusside inhibits thermal hyperalgesia induced by noradrenaline in capsaicin-treated skin.

A facilitatory effect of the sympathetic neurotransmitter noradrenaline on nociceptor discharge may sometimes contribute to pain and hyperalgesia in inflammatory and neuropathic pain syndromes. Our previous studies have shown that noradrenaline heightens sensitivity to heat in skin sensitized by the topical application of capsaicin, and that this effect persists during arterial occlusion (Drummond, P.D., Noradrenaline increases hyperalgesia to heat in skin sensitized by capsaicin, Pain, 60 (1995) 311-315; Drummond, P.D., Independent effects of ischaemia and noradrenaline on thermal hyperalgesia in capsaicin-treated skin, Pain, 67 (1996) 129-133). In the present study, the hyperalgesic effects of arterial occlusion and the vasodilators nitroprusside and isoprenaline were investigated in the capsaicin-treated skin of healthy subjects, to determine whether adrenergic vasoconstriction contributes to thermal hyperalgesia. Thermal hyperalgesia intensified during arterial occlusion; however, sites of noradrenaline iontophoresis were more sensitive to heat than elsewhere in the capsaicin-treated skin, even when noradrenaline was administered during arterial occlusion. Nitroprusside inhibited adrenergic hyperalgesia except during arterial occlusion, suggesting that the analgesic effect of nitroprusside was mediated by vasodilatation. The beta-adrenoceptor agonist isoprenaline did not antagonize the vasoconstrictive or hyperalgesic effects of noradrenaline, and did not influence thermal hyperalgesia elsewhere in the capsaicin-treated skin. These findings favour an ischaemic mechanism of adrenergic hyperalgesia in skin sensitized by capsaicin. An additional mechanism, independent of skin perfusion, is needed to account for the development of adrenergic hyperalgesia during arterial occlusion.

Adolescent↗
PubMed1997

Absence of prostaglandin E2-induced hyperalgesia in NMDA receptor epsilon subunit knockout mice.

1. We have previously found that intrathecal administration of prostaglandins E2 (PGE2) and D2 (PGD2) into conscious mice induced hyperalgesia by the hot plate test. The present study investigated the involvement of N-methyl-D-aspartate (NMDA) receptor in the prostaglandin-induced hyperalgesia by use of mice tacking NMDA receptor epsilon 1, epsilon 4, or epsilon 1/epsilon 4 subunits. 2. PGE2 induced hyperalgesia over a wide range of doses from 50 pg to 500 ng kg-1 in wild-type mice. But PGE2 could not induce hyperalgesia in epsilon 1, epsilon 4, or epsilon 1/epsilon 4 subunit knockout mice. 3. The NMDA receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid (D-AP5), the non-NMDA receptor antagonist 7-D-glutamylaminomethyl sulphonic acid (GAMS), and the nitric oxide synthase inhibitor N epsilon-nitro-L-arginine methyl ester (L-NAME) inhibited the PGE2-induced hyperalgesia in wild-type mice. 4. PGD2 induced hyperalgesia at doses of 25 ng to 250 ng kg-1 in both wild-type and epsilon 1/epsilon 4 subunit knockout mice. The substance P receptor antagonist OP 96.345 blocked the PGD2-induced hyperalgesia in wild-type and epsilon 1/epsilon 4 subunit knockout mice. 5. These results demonstrate that the pathways leading to hyperalgesia are different between PGD2 and PGE2, and that both epsilon 1 and epsilon 4 subunits of the NMDA receptor are involved in the PGE2-induced hyperalgesia.

Animals↗
PubMed2001

Differential roles of spinal neurokinin 1/2 receptors in development of persistent spontaneous nociception and hyperalgesia induced by subcutaneous bee venom injection in the conscious rat.

To evaluate the roles of spinal neurokinin receptors in the development of persistent nociception and hyperalgesia to thermal and mechanical stimuli induced by subcutaneous (s.c.) bee venom injection, effects of intrathecal (i.t.) pre- or post-treatment with a non-selective antagonist of (NK1/2) receptors, [D-Arg1,D-Trp7,9,Leu11] substance P (spantide), and a selective NK3 receptor antagonist, (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methyl acetamide (SR142801) were assessed in conscious rat. Injection of bee venom s.c. into the plantar surface of one hind paw resulted in a pathological pain phenomenon characterized by a 1-2 h single phase of persistent spontaneous nociceptive behaviors (continuously flinching the injected paw) and a 72-96 h profound primary thermal and mechanical hyperalgesia in the injection site and a secondary thermal hyperalgesia in the non-injected hindpaw. Pre-treatment with spantide i.t. at 0.05 microg, 0.5 microg and 5 microg produced a dose-related suppression of the bee venom-induced flinching reflex during the whole time course and the inhibitory rate was 24 +/- 12.60% (35.38 +/- 4.12 flinches/5 min, n=5), 48 +/- 6.75% (24.53 +/- 2.90 flinches/5 min, n=5) and 60 +/- 7.69% (18.88 +/- 3.58 flinches/5 min, n=5) respectively when compared with the saline control group (46.80 +/- 2.60 flinches/5 min, n=5). Post-treatment of spantide i.t. at the highest dose (5 microg) used in the present study 5 min after bee venom injection also produced a 49% suppression of the flinching reflex in the control group [post-spantide vs saline: 19.42 +/- 3.15 (n=5) vs 38.42 +/- 3.25 flinches/5 min (n=5)]. Moreover, i.t. pre-treatment with 5 microg spantide partially prevented the primary and secondary thermal hyperalgesia from occurring, while it did not show any influence on the development of primary mechanical hyperalgesia. Neither the established thermal nor mechanical hyperalgesia identified in the above sites was affected by i.t. post-treatment with the same dose of spantide 3 h after bee venom injection. Pre and post-treatment of SR142801 did not produce any significant effect on the bee venom-induced spontaneous pain and thermal and mechanical hyperalgesia. Our present result suggests that activation of spinal NK1/2 receptors is involved in both induction and maintenance of the persistent spontaneous nociception, while it is only involved in induction of the primary and secondary thermal, but not primary mechanical hyperalgesia induced by s.c. bee venom injection. The spinal NK3 receptor seems not likely to be involved in the bee venom-induced behavioral response characterized by spontaneous pain and thermal and mechanical hyperalgesia.

Analgesics↗
PubMed1992

The plasticity of cutaneous hyperalgesia during sympathetic ganglion blockade in patients with neuropathic pain.

In order to investigate the plasticity of cutaneous sensory abnormalities in neuropathic pain, we monitored sensory and vasomotor effects of diagnostic sympathetic ganglion blocks in 24 patients, who suffered from chronic pain and cutaneous hyperalgesia following peripheral nerve or tissue injury. Ongoing pain was rated on a visual analogue scale, and pain evoked by innocuous tactile and cooling stimuli (hyperalgesia) on a verbal rating scale. Skin temperatures were determined at symmetric sites. In two patients, cutaneous blood flow was measured with a laser Doppler device. The sympathetic blocks led to a significant reduction of the group mean ongoing pain (40%) and cutaneous hyperalgesia (50%). Between patients, however, there was a large variability that could not be related merely to adequacy of sympathetic blockade. Neither the magnitude of change in skin temperature nor the final skin temperature after the block correlated with the amount of pain relief. The relief of hyperalgesia, however, correlated with the relief of ongoing pain. Nine patients experienced pain relief of greater than 50%. In these patients, the time course of hyperalgesia relief was similar to the time course of relief of ongoing pain. Pain relief occurred simultaneously with or a few minutes before cutaneous vasodilatation. During the block, even vigorous mechanical or cold stimuli did not rekindle hyperalgesia. In all patients, pain and hyperalgesia returned within a day after the block. In three patients tested, passive warming of the limb to the temperature achieved by the sympathetic block had negligible effects on pain and hyperalgesia. The hyperalgesia of sympathetically maintained pain is thought to be due to sensitization of central pain-signalling neurons to mechanoreceptor input. The present data indicate that this sensitization is highly plastic even when the disease has persisted for months or years. It could be reversed within minutes by a sympathetic blockade, but returned when sympathetic block subsided. Mechanoreceptor input by itself was not sufficient to maintain or rekindle the central sensitization. This supports the hypothesis that low-grade activity of nociceptors, possibly due to development of alpha-adrenergic sensitivity after injury, is involved in the maintenance of central sensitization.

Adult↗
PubMed2001

Opioid-induced hyperalgesia and incisional pain.

UNLABELLED: Opioids occupy a position of unsurpassed clinical utility in the treatment of pain of many etiologies. However, recent reports in laboratory animals and humans have documented the occurrence of hyperalgesia when the administration of opioids is abruptly tapered or discontinued, a condition known as opioid-induced hyperalgesia (OIH). In these studies we documented that rats administered morphine (40 mg. kg(-1). day(-1) for 6 days) via subcutaneous osmotic minipumps demonstrated thermal hyperalgesia and mechanical allodynia for several days after the cessation of morphine administration. Additional experiments using a rat model of incisional pain showed that that attributable to OIH were additive with the hyperalgesia and allodynia that resulted from incision. In our final experiments we observed that if naloxone is administered chronically before incision then discontinued (20 mg. kg(-1). day(-1) for 6 days), the hyperalgesia and allodynia that result from hind paw incision was markedly reduced. In contrast, naloxone 1 mg/kg administered acutely after hind paw incision increased hyperalgesia and allodynia. We conclude that the chronic administration of exogenous opioid receptor agonists and antagonists before incision can alter the hyperalgesia and allodynia observed in this pain model, perhaps by altering intrinsic opioidergic systems involved in setting thermal and mechanical nociceptive thresholds. IMPLICATIONS: The chronic administration of opioids followed by abrupt cessation can lead to a state of hyperalgesia. In these studies we demonstrate that the hyperalgesia from opioid cessation and from hind paw incision are additive in rats. We suggest that failure to take into consideration preoperative opioid use can lead to excessive postoperative pain.

Analgesics, Opioid↗
PubMed1999

Spinal antinociceptive effect of epidural nonsteroidal antiinflammatory drugs on nitric oxide-induced hyperalgesia in rats.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) suppress various hyperalgesia perhaps via inhibition of cyclooxygenase activity at the spinal cord. The present study aimed to examine whether epidural application of NSAIDs affects hyperalgesia induced by nitric oxide. METHODS: The authors studied the antinociceptive effects of epidurally administered NSAIDs in rats with a chronically in-dwelling epidural catheter by three hyperalgesic models, including nitric oxide-induced hyperalgesia by nitroglycerin (10 microg) or l-arginine (100 microg), and the biphasic response in the formalin test. RESULTS: Epidural, but not systemic, nitroglycerin induced hyperalgesia that was completely blocked by methylene blue but not by N(omega)-nitro-L-arginine methyl ester (L-NAME). Epidural l-arginine, but not d-arginine, also induced hyperalgesia that was completely blocked by L-NAME. Epidural S(+)ibuprofen (100-1,000 microg) suppressed the nitroglycerin- and l-arginine-induced thermal hyperalgesia and also the second phase response in the formalin test. Neither systemic S(+)ibuprofen nor epidural R(-)ibuprofen suppressed the hyperalgesia Epidural indomethacin (10-100 microg) or diclofenac (10-1,000 microg) dose-dependently suppressed nitroglycerin-induced thermal hyperalgesia The order of potency for this suppression (ID50 in microg) was indomethacin = didofenac > S(+)ibuprofen >> R(-)ibuprofen. CONCLUSIONS: The antinociceptive action of epidurally administered NSAIDs could be the result of suppression of spinal sensitization, perhaps induced with nitric oxide in the spinal cord. The ID50 values for epidural indomethacin, diclofenac, and S(+)ibuprofen were about 10 times higher than those reported in other studies for intrathecal NSAIDs in hyperalgesia models. (Key words: Cyclooxygenase inhibitors; NO donor; NO precursor; optical isomers; neuroplasticity.)

Animals↗
PubMed1995

Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia.

1. Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2. To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3. The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4. Systemic dexamethasone (120 micrograms kg-1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg-1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg-1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5. The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose. 6. The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7. Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 microgram, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum. 8. IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta. 9. Intraplantar NGF (0.02, 0.2 and 2 microg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1beta levels in the hindpaw skin.10. Our results demonstrate that IL-1beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.

Animals↗
PubMed2006

A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators.

The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4(-/-) knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C epsilon, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.

Animals↗
PubMed1985

The role of the polymorphonuclear leukocyte in hyperalgesia.

The results of recent studies of the mechanism of leukotriene B4-induced hyperalgesia suggest a dependence on polymorphonuclear leukocytes (PMNLs). In this study, we addressed the contribution of PMNLs to hyperalgesia evoked by the peptide chemotactic factors N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the anaphylatoxin fragment of the fifth component of the complement pathway (C5a). Local injection of glycogen, which attracts but does not activate PMNLs, produced a marked shift to the left (toward lower concentrations) in the concentration dependence curve of fMLP-induced hyperalgesia. In addition, PMNL repletion by transfusion with syngeneic PMNLs reestablished fMLP-induced hyperalgesia in PMNL-depleted rats. Finally, supernatants from rat and human PMNLs, that had been stimulated with fMLP in vitro, produced hyperalgesia in PMNL-depleted rats. Preliminary characterization of the hyperalgesia-inducing activity released by stimulated PMNLs indicated that it is lipid in nature. The nonsteroidal anti-inflammatory indomethacin did not attenuate C5a and fMLP-induced hyperalgesia. Thus, the hyperalgesia produced by fMLP and C5a is similar to that produced by leukotriene B4 in that it is dependent on PMNLs and independent of the cyclo-oxygenation of arachidonic acid. Taken together, these data suggest that structurally diverse PMNL-chemotactic factors produce hyperalgesia by a novel mechanism, involving PMNL-derived factors.

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