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PubMedDate not supplied

Comparison of generalized and localized hyperalgesia in patients with recurrent headache and fibromyalgia.

OBJECTIVES: Research suggests that dysregulated pain modulation may play an important role in recurrent headaches and fibromyalgia syndrome (FMS). The primary objective of this study was to investigate algesic responses in localized cervical and pericranial regions (ie, headache-specific areas) and distal locations (ie, trochanter and gluteal) in patients with primary headaches (tension-type and migraine). The headache patients' algesic responses were compared with those of a sample of patients with musculoskeletal pain who report generalized hyperalgesia, or FMS. METHODS: Seventy patients with mixed headache diagnoses and 66 patients with FMS underwent a standardized examination of generalized hyperalgesia based on American College of Rheumatology criteria. RESULTS: Twenty-eight of the 70 headache patients reported the presence of widespread TP pain, suggesting generalized hyperalgesia. Headache diagnosis was unrelated to the presence or absence of generalized hyperalgesia. The subset of headache patients with generalized hyperalgesia did not differ from the FMS patients in pain sensitivity in the cervical and pericranial areas. Regression analyses revealed that pressure pain sensitivity was significantly related to self-reported pain only in the headache patients with generalized hyperalgesia. CONCLUSIONS: These results suggest that extensive dysregulation in pain modulation is important for a substantial minority of recurrent headache patients, who seem to be quite similar to FMS patients. Differential treatment planning targeting generalized hyperalgesia may be useful in treating headache patients exhibiting generalized hyperalgesia more effectively.

Adult↗
PubMed2005

Estrogen regulates adrenal medullary function producing sexual dimorphism in nociceptive threshold and beta-adrenergic receptor-mediated hyperalgesia in the rat.

Epinephrine produces sexually dimorphic beta(2)-adrenergic receptor-mediated mechanical hyperalgesia, with male rats exhibiting greater hyperalgesia. Because female rats have higher plasma epinephrine levels, and beta-adrenergic receptor sensitivity is affected by chronic exposure to agonists, we tested the hypothesis that this sexual dimorphism is due to epinephrine-induced desensitization of beta(2)-adrenergic receptors. Following gonadectomy, epinephrine hyperalgesia, as measured by the Randall-Selitto paw-withdrawal test, was unchanged in male rats while in females it was increased. Prepubertal male and female rats do not demonstrate sexual dimorphism in either plasma epinephrine level or epinephrine-induced hyperalgesia. Adrenal medullectomy and adrenal denervation both significantly enhanced epinephrine hyperalgesia, but only in females. In contrast, the sexually dimorphic hyperalgesia induced by prostaglandin E(2), another agent that acts directly to sensitize primary afferent nociceptors, was not enhanced by adrenal medullectomy or denervation. Chronic administration of epinephrine in male rats, to produce plasma levels similar to those of gonad-intact females, significantly attenuated epinephrine-induced hyperalgesia, making it similar to that in females. These results strongly support the suggestion that estrogen regulates plasma epinephrine in female rats and differential sensitivity to beta(2)-adrenergic agonists accounts for the sexual dimorphism in epinephrine-induced hyperalgesia. Unexpectedly, regulation of adrenal medullary function by estrogen was also found to modulate baseline nociceptive threshold such that females had a lower nociceptive threshold.

Adrenal Medulla↗
PubMed2002

Hyperalgesia and neural excitability following injuries to central and peripheral branches of axons and somata of dorsal root ganglion neurons.

We examined thermal hyperalgesia, excitability of dorsal root ganglion (DRG) neurons, and antinociceptive effects of N-methyl-d-aspartate (NMDA) receptor antagonists in rats with injury to different regions of DRG neurons. The central or peripheral branches of axons of DRG neurons were injured by partial dorsal rhizotomy (PDR) and chronic constriction injury of sciatic nerve (CCI), respectively, or the somata injured by chronic compression of DRG (CCD). Thermal hyperalgesia was evidenced by significantly shortened latencies of foot withdrawal to radiant heat stimulation of the plantar surface. Intracellular recordings were obtained in vitro from L(4) and/or L(5) ganglia. There are four principle findings: 1) PDR as well as CCD and CCI induced thermal hyperalgesia; 2) PDR produced significantly less severe and shorter duration hyperalgesia than CCD and CCI; 3) intrathecal administration of NMDA receptor antagonists d-2-amino-5-phosphonovaleric acid (APV) and dizocilpine maleate (MK-801) inhibited thermal hyperalgesia in PDR, CCD, and CCI rats. Pretreatment of APV and MK-801 delayed the emergence of hyperalgesia for 48-72 h, while posttreatment inhibited hyperalgesia for 24-36 h; and 4) CCD and CCI increased excitability of DRG neurons as judged by the significantly lowered threshold currents and action potential voltage thresholds and increased incidence of repetitive discharges. However, PDR did not alter the excitability of DRG neurons. These findings indicate that injury to the dorsal root, compared with injury to the peripheral nerve or DRG somata has different effects on the development of hyperalgesia. These contributions involve different changes in DRG membrane excitability, but each involves pathways (presumably in the spinal cord) that depend on NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1997

Cyclosporin inhibits hyperalgesia and edema in arthritic rats: role of the central nervous system.

Since arthritis induced by Mycobacterium products (adjuvant) in rats is considered to be immunologically driven, the objective of the present study was to determine if the immunosuppressor drug cyclosporin could affect hindpaw edema and joint hyperalgesia simultaneously. Female Holtzman rats (140-170 g) presented hyperalgesia and edema on the 8th and 12th day following adjuvant injection. Daily systemic (oral or intramuscular) administration of cyclosporin (0.5-5.0 mg kg (-1) day (-1)) or dexamethasone (0.01-0.1 mg kg (-1) day (-1)) for 15 days starting on day zero dose-dependently inhibited the hindpaw edema and hyperalgesia in arthritic rats. However, hyperalgesia but not edema could be detected two days after cyclosporin withdrawal. We concluded that a) the continuous presence of cyclosporin is essential to reduce the development of joint hyperalgesia and that b) different mechanisms underlie the appearance of hyperalgesia and edema in this model. The intracerebroventricular (i.c.v.) administration of 5-50-fold smaller doses of cyclosporin (1.5-150 micrograms/day) or dexamethasone (15 micrograms/day) also reduced the arthritic hindpaw edema and hyperalgesia. Peripheral blood from animals injected with effective systemic cyclosporin doses showed detectable levels of the drug, whereas peripheral blood from those injected with i.c.v. cyclosporin did not, as measured by specific RIA. Our results indicate that cyclosporin administered by the central route is as effective as by the systemic route to reduce joint hyperalgesia and hindpaw edema in arthritic rats. The antiarthritic effect induced by low doses of cyclosporin in the central nervous system (CNS) could be explored to avoid it often associated systemic side effects during chronic therapy. However, the mechanism(s) involved in the antiarthritic response to cyclosporin in the CNS remain to be elucidated.

Animals↗
PubMed2001

Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.

This study characterizes an animal model of persistent mechanical hyperalgesia induced by repeated intramuscular injections of low pH saline. Saline at pH 4, 5, 6, or 7.2 was injected twice, 2 to 10 days apart, into the gastrocnemius muscle of rats. To quantify hyperalgesia, paw withdrawal latency to radiant heat (heat hyperalgesia) and withdrawal threshold to mechanical stimuli (mechanical hyperalgesia) were measured. Two unilateral injections of low pH saline, 5 days apart, caused a pH-dependent bilateral mechanical, but not heat, hyperalgesia that lasted 30 days. Injections given 2 and 5 days apart produced a significantly greater mechanical hyperalgesia than injections given 10 days apart. Lidocaine injection into the gastrocnemius muscle or unilateral dorsal rhizotomy, 24 h after the second injection (pH 4), had no effect on the contralateral mechanical hyperalgesia. Minimal histopathology was observed in the injected muscle, and changes were similar between groups injected with pH 4 and pH 7.2. Thus, this new model of widespread, chronic muscle-induced pain is unrelated to tissue damage and is not maintained by continued primary afferent input from the site of injury.

Animals↗
PubMed1997

Involvement of interleukin-1 beta, nerve growth factor, and prostaglandin-E2 in the hyperalgesia induced by intraplantar injections of low doses of thymulin.

The effect of various doses of intraplantar thymulin injection, on nociceptive thresholds, in the hind paw of rats was assessed using different pain tests. As little as 0.5 ng thymulin resulted in localized mechanical hyperalgesia as assessed by the paw pressure test and thermal hyperalgesia as assessed by the paw immersion, hot plate, and tail flick tests. The highest dose of thymulin (10 ng) reduced both paw pressure and paw immersion latencies in the noninjected paw also. Thymulin (5 ng) also resulted in significant elevation in the levels of interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the injected paw. Both dexamethasone and indomethacin reversed thymulin-induced hyperalgesia. Also interleukin-1 receptor antagonist (IL-1ra) and a polyclonal anti-NGF antiserum significantly reduced thymulin-induced hyperalgesia. On the other hand, the tripeptide lys-D-pro-val (known to antagonize IL-1 beta and PGE2 induced hyperalgesia) reversed the hyperalgesia due to thymulin. In conclusion, thymulin induces localized hyperalgesia which is mediated by PGE2-dependent mechanisms and this pathway could be either partially dependent on or totally independent of IL-1 beta mechanisms.

Animals↗
PubMed1998

Effect of colchicine on nerve growth factor-induced leukocyte accumulation and thermal hyperalgesia in the rat.

In addition to its neuronal effects, nerve growth factor (NGF) is known to act on inflammatory and immune cells. The aim of the present study was to investigate the effect of colchicine on NGF-induced leukocyte accumulation and thermal hyperalgesia. Initial experiments showed that intradermal injection of recombinant human (rh) NGF (0.8 and 4 microg) caused a longlasting increase in tissue myeloperoxidase (MPO) indicating leukotactic activity of NGF. Colchicine (0.3 and 1 mg/kg) attenuated the NGF (0.8 and 4 microg)-induced increase in tissue myeloperoxidase (MPO) as determined 6 h after NGF application. Intraplantar injection of NGF into the rat hindpaw caused a decrease in thermal nociceptive threshold, which, at 4 microg NGF, was accompanied by moderate (about 35% increase in paw volume) edema. The thermal hyperalgesia was evident 20 min after injection and lasted less than 4 h. Colchicine (0.3 and 1 mg/kg) had no significant effect on NGF-induced edema, but reduced NGF-induced thermal hyperalgesia. Colchicine (1 mg/kg) did not significantly reduce thermal hyperalgesia produced by intraplantar bradykinin, prostaglandin E1, or 5-hydroxytryptamine. Treatment of rats with a dose of indometacin (2 mg/kg) that was sufficient to block cyclooxygenase had no significant effect on NGF-induced thermal hyperalgesia or edema. In vitro, colchicine (0.4-12 microg/ml) did not significantly influence NGF (10 ng/ml)-induced histamine release from rat peritoneal cells, suggesting that a mast cell stabilizing effect of colchicine did not contribute to inhibition of NGF-induced thermal hyperalgesia. The results show that NGF causes localized indometacin-resistant thermal hyperalgesia that can be blocked by the microtubule disrupting agent colchicine. These results raise the possibility that a mechanism by which NGF produces peripheral sensitization is related to its leukotactic effect.

Animals↗
PubMed1996

Different roles of alpha 2-adrenoceptors of the medulla versus the spinal cord in modulation of mustard oil-induced central hyperalgesia in rats.

We attempted to determine the roles of spinal versus medullary alpha 2-adrenoceptors in modulation of central hyperalgesia in rats. Central hyperalgesia was produced by applying mustard oil (50%) to the skin of the ankle of one hindpaw. The threshold for eliciting a hindlimb flexion reflex was determined by applying a series of calibrated monofilaments to the glabrous skin of the hindpaw contralaterally (= control) or ipsilaterally to the mustard oil-treated ankle (= outside the area of primary hyperalgesia). Medetomidine (an alpha 2-adrenoceptor agonist; 1 micrograms), atipamezole (an alpha 2-adrenoceptor antagonist; 2.5 micrograms) or saline was microinjected into the lateral reticular nucleus of the medulla, the nucleus raphe magnus, or intrathecally to the lumbar spinal cord 12 min before the mustard oil treatment. Following saline injections, mustard oil produced a significant decrease of the hindlimb withdrawal threshold in the mustard oil-treated limb but not in the contralateral limb. Atipamezole in the lateral reticular nucleus produced a complete reversal of the hyperalgesia but no effect on the threshold of the intact limb. However, atipamezole in the raphe magnus nucleus or in the lumbar spinal cord did not produce a significant attenuation of the hyperalgesia. Medetomidine in the spinal cord, but not in the lateral reticular nucleus, reversed the hyperalgesia. At this dose range (up to 3 micrograms), medetomidine in the spinal cord of nonhyperalgesic control rats did not produce any significant change in the withdrawal response of hindlimbs or in the tail-flick latency. The results indicate that neurogenic inflammation induces significant plastic changes in the function of alpha 2-adrenergic pain regulatory mechanisms. In rats with mustard oil-induced central hyperalgesia, an alpha 2-adrenoceptor antagonist produces an antihyperalgesic effect due to an action on the caudal ventrolateral medulla, whereas an alpha 2-adrenoceptor agonist produces an enhanced antinociceptive effect due to a direct action on the spinal cord.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1994

Induction of B1 receptors in vivo in a model of persistent inflammatory mechanical hyperalgesia in the rat.

The induction of mechanical hyperalgesia by B1 and B2 receptor agonists following an inflammatory insult has been studied in the rat. Intra-articular injection of bradykinin, but not desArg9 bradykinin, into naïve joints induced mechanical hyperalgesia with a reduction of up to 38% in load tolerated by the treated leg. Following intra-articular injection of Freund's complete adjuvant (FCA) the load tolerated by the treated leg was depressed for three days. The development of FCA-induced hyperalgesia was reduced by desArg9Leu8BK or Hoe 140. Bradykinin, desArg9BK and the metabolically stable B1 receptor agonist SarDPhe8desArg9BK were all hyperalgesic upon intra-articular administration 3 days after FCA administration. The hyperalgesia induced by desArg9BK and SarDPhe8desArg9BK was prevented by co-administration of desArg9Leu8BK but not by Hoe 140. At low doses (< 10 nmol) bradykinin-induced hyperalgesia was presented by Hoe 140 but not by desArg9Leu8BK. At higher doses of bradykinin (> 100 nmol) the hyperalgesia was reduced by both Hoe 140 and desArg9Leu8BK. These data suggest that following an inflammatory insult both bradykinin B1 and B2 receptor mechanisms are involved in the accompanying hyperalgesia.

Animals↗
PubMed1991

Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.

Administration, Cutaneous↗
PubMed1992

Intracerebroventricular micro-injections of non-steroidal anti-inflammatory drugs abolish reperfusion hyperalgesia in the rat's tail.

Prostaglandins are mediators of reperfusion hyperalgesia; their site of action may be in the periphery, in the central nervous system, or both. We have investigated whether prostaglandins play a role in the central nervous system during reperfusion hyperalgesia, by intracerebroventricular (i.c.v.) micro-injection of non-steroidal anti-inflammatory drugs (NSAID), to inhibit local prostanoid synthesis. We induced tail ischaemia in conscious rats by applying an inflatable cuff at the base of the tail. The cuff was released at the first signs of co-ordinated escape behaviour. Responses to a noxious thermal stimulus were assessed, by measuring tail flick latency following immersion of the tail in water at 49 degrees C, prior to and immediately after release of the tourniquet. Tail flick latency decreased significantly following ischaemia, that is there was post-ischaemic reperfusion hyperalgesia. Intracerebroventricular micro-injection of NSAID prior to applying the tourniquet had no effect on the co-ordinated escape behaviour during ischaemia or on the tail flick latency after application of a sham tourniquet (uninflated cuff). However all the drugs abolished the hyperalgesia evident during reperfusion. Doses required to abolish hyperalgesia were 0.001 mg/kg indomethacin, 0.08 mg/kg dipyrone, 0.09 mg/kg ibuprofen, 0.2 mg/kg diclofenac sodium and 0.2 mg/kg paracetamol. These doses are 2-3 orders of magnitude less than those necessary to abolish reperfusion hyperalgesia when the same drugs are administered systemically. Our results indicate that the development of reperfusion hyperalgesia of the rat's tail depends on the synthesis of prostanoids within the central nervous system.

Animals↗
PubMed1993

Dissociated secondary hyperalgesia in a subject with a large-fibre sensory neuropathy.

In the skin surrounding a site of injury, hyperalgesia develops to mechanical stimuli. Two types of secondary hyperalgesia (to light touch and punctate stimuli) have recently been differentiated, based on different durations and sizes of the area involved. We studied secondary hyperalgesia in a subject who had a loss of myelinated afferent nerve fibres below the neck that spared the A delta group. Stroking with a cotton swab was not perceived anywhere on affected skin either before or after injection of 60 micrograms of capsaicin. Thus, there was no hyperalgesia to light touch. Capsaicin injection into the volar forearm evoked normal pain and flare. A von Frey probe exerting a force of 40 mN was perceived as sharp. The sensation of sharpness was more pronounced up to 2 cm outside the flare zone for at least 16 min following the injection (tested with a 200 mN von Frey probe). Thus, hyperalgesia to punctate stimuli developed as in healthy subjects. These data support the model that hyperalgesia to light touch (allodynia) is due to sensitisation of central pain-signaling neurones to low-threshold mechanoreceptor input (A beta fibres). In contrast, punctate hyperalgesia is likely to be due to sensitisation to nociceptor input (A delta or C fibres).

Adult↗
PubMed1995

Peripheral hyperalgesia in experimental neuropathy: mediation by alpha 2-adrenoreceptors on post-ganglionic sympathetic terminals.

Rats in which the sciatic nerve is partially transected develop hyperalgesia which is relieved by sympathectomy. We carried out experiments using this model of experimental peripheral neuropathy to examine the peripheral mechanisms underlying sympathetically maintained pain. Subcutaneous injection of noradrenaline (NA) into the affected paw exacerbated the hyperalgesia but had no effect in control animals. Injection of the non-specific alpha-adrenergic blocker phentolamine and the alpha 2-adrenergic blocker yohimbine significantly relieved the hyperalgesia, while injection of the alpha 1-adrenergic blocker prazosin had no effect. Peripheral injection of the alpha 2-adrenergic agonist clonidine had no significant effect, while injection of the alpha 1-adrenergic agonist phenylephrine produced slight exacerbation of mechanical hyperalgesia. Hyperalgesia was eliminated by peripheral injection of indomethacin into the affected paw. Following a chemical sympathectomy, hyperalgesia was eliminated and injection of NA into the hyperalgesic paw had no effect on pain thresholds. We concluded that NA exacerbates hyperalgesia in this experimental model by acting on alpha 2-adrenoreceptors which are located on post-ganglionic sympathetic terminals. Our results are consistent with the proposal (Levine et al. 1986) that activation of these adrenoreceptors brings about an increased release of prostaglandins which sensitises nociceptors.

Adrenergic alpha-Agonists↗
PubMed1996

Independent effects of ischaemia and noradrenaline on thermal hyperalgesia in capsaicin-treated skin.

Noradrenaline increases thermal hyperalgesia in skin previously sensitized by capsaicin. The aim of the present study was to determine whether a vasoconstrictor ischaemic effect of noradrenaline increases thermal hyperalgesia. Heat pain thresholds were measured in the capsaicin-treated and untreated skin on the forearms of 13 normal volunteers. The iontophoresis of noradrenaline induced thermal hyperalgesia in untreated skin (mean heat pain threshold at the noradrenaline site 42.2 +/- 4.2 degrees C compared with 47.3 +/- 3.5 degrees C at control sites, P < 0.001), and increased thermal hyperalgesia in capsaicin-treated skin (mean heat pain threshold at the noradrenaline site 38.6 +/- 2.1 degrees C compared with 45.7 +/- 5.6 degrees C at control sites, P < 0.001). Heat pain thresholds did not change during venous congestion, induced by applying a cuff pressure of 60 mmHg to the upper arm. Increasing the cuff pressure to 200 mmHg decreased the heat pain threshold by 2.4 +/- 2.3 degrees C at control sites in the capsaicin-treated skin (P < 0.01); nevertheless, thermal hyperalgesia was greater at the noradrenaline site than at control sites during arterial occlusion, both in capsaicin-treated and untreated skin (in the capsaicin-treated skin, mean heat pain threshold during arterial occlusion 38.1 +/- 3.3 degrees C at the noradrenaline site compared with 43.4 +/- 6.5 degrees C at control sites, P < 0.001; in the untreated skin, mean heat pain threshold at the noradrenaline site 44.3 +/- 3.6 degrees C compared with 47.9 +/- 3.1 degrees C at control sites, P < 0.001). Thermal hyperalgesia subsided in control sites in the capsaicin-treated skin after cuff pressure was released, but persisted at sites of noradrenaline iontophoresis (in the capsaicin-treated skin, mean heat pain threshold during reactive hyperaemia 45.2 +/- 5.1 degrees C at the noradrenaline site compared with 49.3 +/- 6.0 degrees C at control sites, P < 0.01; in the untreated skin, mean heat pain threshold at the noradrenaline site 46.5 +/- 3.3 degrees C compared with 48.8 +/- 3.0 degrees C at control sites, P < 0.001). Arterial occlusion could increase thermal hyperalgesia in capsaicin-treated skin by preventing the dispersal of nociceptive substances peripherally or through central summation of nociceptive signals. The hyperalgesic effect of noradrenaline is greater than the hyperalgesic effect of ischaemia, suggesting that some mechanism in addition to vasoconstriction contributes to the nociceptive effect of noradrenaline.

Adult↗
PubMed1992

Mediation of serotonin hyperalgesia by the cAMP second messenger system.

In this study we have evaluated the second messenger system that might couple 5-HT1A receptor activation to produce peripheral hyperalgesia. The intradermal injection of the serotonin (5-hydroxytryptamine; 5-HT) receptor agonist for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH DPAT) produces a dose-dependent hyperalgesia which was attenuated by a cAMP kinase inhibitor (the R-isomer of cyclic adenosine-3'-5'-monophosphate), but prolonged by the inhibition of endogenous phosphodiesterase by rolipram, supporting a role for the cAMP second messenger system. The 5-HT1A receptor agonist, 8-OH-DPAT, and the adenyl cyclase activator, forskolin administered together, produced an additive hyperalgesia, suggesting that the 5-HT1A receptor in peripheral terminals of the primary afferent neurons is positively coupled to the cAMP second messenger system in producing hyperalgesia. The inability of pertussis toxin to inhibit 8-OH DPAT-induced hyperalgesia further supports this hypothesis. The coupling of the 5-HT1A receptor to the cAMP second messenger system appears to be through guanine regulatory proteins since guanosine 5'-O-(3-thiotriphosphate) and cholera toxin both markedly enhanced 8-OH DPAT hyperalgesia. In further support of the role of guanine nucleotide regulatory proteins, guanosine 5'-O-(2-thiodiphosphate), as well as activators of inhibitory guanine regulatory proteins (the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, and the adenosine A1 agonist, N6-cyclopentyladenosine, significantly attenuated 8-OH DPAT hyperalgesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Is there more than one prostaglandin E receptor subtype mediating hyperalgesia in the rat hindpaw?

Five synthetic prostaglandin E analogs (11-deoxyPGE1, 17-phenyl-ol-trinor prostaglandin E2, enisoprost, MB28767 and misoprostol) have been evaluated for their ability to produce mechanical hyperalgesia in rats. The Randall-Selitto paw withdrawal model of mechanical hyperalgesia was used. Following intradermal injections (2.5 microliters) into the dorsal surface of the hindpaw, each prostaglandin E analog produced a dose-dependent (1-1000 ng) decrease in nociceptive threshold (i.e. hyperalgesia). Hyperalgesia produced by 17-phenyl-ol-trinor prostaglandin E2 and MB28767, was inhibited by the prostaglandin E1 antagonist SC19220 (7.5 ng), while the hyperalgesia produced by 11-deoxyprostaglandin E1, enisoprost and misoprostol was not inhibited by this antagonist. Hyperalgesia produced by all five analogs was significantly attenuated or completely blocked by inhibiting stimulatory guanine nucleotide-binding regulatory protein with guanosine 5'-O-(2-thiodiphosphate), adenylyl cyclase with 2'5'-dideoxyadenosine and protein kinase A with WIPTIDE. These results suggest the presence of more than one prostaglandin E-receptor subtype, which mediate hyperalgesia, predominantly via the cAMP second messenger system, in the hindpaw of the rat.

Alprostadil↗
PubMed1994

Comparison of prostaglandin E1- and prostaglandin E2-induced hyperalgesia in the rat.

We have studied prostaglandin E1-induced mechanical hyperalgesia in the rat hindpaw, by assessing paw-withdrawal thresholds, before and after injecting prostaglandin E1 alone or with other agents, in normal and streptozotocin-induced diabetic rats. In normal and diabetic rats, prostaglandin E1 (1-1000 ng) produced a dose-dependent decrease in mechanical nociceptive threshold. In diabetic rats, prostaglandin E1 was more potent than in normal rats, in producing hyperalgesia, whereas prostaglandin E2 hyperalgesia was not changed in normal and diabetic rats. Prostaglandin E1-induced hyperalgesia was not inhibited by E-type 1 prostaglandin receptor antagonists, SC19220 or SC51089, either in normal or diabetic rats. In fact, in the presence of SC19220, prostaglandin E1 produced enhanced hyperalgesia, in normal rats. Prostaglandin E1 hyperalgesia was not significantly modified by sympathectomy or indomethacin. Unlike prostaglandin E2, prostaglandin E1 hyperalgesia was not blocked by the inhibitor of the stimulatory guanine nucleotide-binding regulatory protein, guanosine 5'-O-(2-thiodiphosphate). It is suggested that prostaglandin E1 decreases primary afferent nociceptive threshold directly, by activating a prostaglandin receptor other than the E-type 1 prostaglandin receptor, and that this receptor is not coupled to a stimulatory guanine nucleotide-binding regulatory protein.

Alprostadil↗
PubMed2004

Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation.

Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by mu and delta opioid receptors at 2-15 Hz and by kappa opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against mu (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta (naltrinodole, NTI) and kappa (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by mu- and delta- but not kappa-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of mu and delta, but not kappa, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.

Analgesics, Opioid↗