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Biomedical subjects

Jana Sawynok

Publications and source records attributed to Jana Sawynok.

At least 19 recordsLinked to original sources
PubMed2006

Pain behaviors produced by capsaicin: influence of inflammatory mediators and nerve injury.

UNLABELLED: The present study was undertaken to characterize spontaneous (ie, nonevoked) pain behaviors (flinching, biting/licking) produced by local injections of capsaicin into the rat hindpaw as a model of chemogenic pain, and to determine effects of inflammatory mediators and nerve injury on such behaviors. Capsaicin antagonists are a potential class of novel topical analgesics, and this model may be of value for preclinical screening of novel compounds. Local injections of capsaicin (0.1-30 microg) into the hindpaw produced flinching and biting/licking behaviors over 5 min, and these were reduced by capsazepine, a competitive antagonist for capsaicin at the TRPV1 receptor. Coadministration of noradrenaline (NA), prostaglandin E(2) (PGE(2)), and 5-hydroxytryptamine (5-HT) augmented capsaicin-evoked responses primarily by extending the duration of behaviors. Partial sciatic nerve ligation decreased flinching produced by capsaicin alone, by capsaicin in combination with each of NA, PGE(2), and 5-HT, and by formalin. Tibial nerve injury also reduced capsaicin-evoked flinching, and responses to formalin, but spinal nerve ligation did not affect either. These results indicate that (1) spontaneous pain behaviors occur as a result of TRPV1 receptor activation with a different time course than evoked responses, (2) inflammatory mediators augment capsaicin-evoked pain behaviors, and (3) various forms of nerve injury produce different effects on capsaicin-evoked pain behaviors. PERSPECTIVE: The VR1 receptor is a potential target for development of novel topical analgesics. This study characterized pain behaviors produced by local injections of capsaicin in the presence of inflammatory mediators and following various forms of nerve injury. Results are of interest for the preclinical screening of novel VR1 receptor antagonists.

Animals↗
PubMed2005

Amitriptyline enhances extracellular tissue levels of adenosine in the rat hindpaw and inhibits adenosine uptake.

Local administration of amitriptyline into the rat hindpaw produces peripheral antinociception; this is reduced by adenosine receptor antagonists and appears to involve endogenous adenosine. The present study used peripheral microdialysis: (a) to determine whether amitriptyline could enhance extracellular tissue levels of endogenous adenosine in the rat hindpaw and (b) to examine mechanisms by which such an increase could occur. Local injection of amitriptyline into the plantar hindpaw, at doses that produce peripheral antinociception (100-300 nmol), produced an increase in local extracellular levels of adenosine. When injected in combination with formalin, which also enhances such levels of adenosine, an additive increase was observed. This adenosine originated partly as nucleotide, as inhibition of ecto-5'-nucleotidase reduced the amount of adenosine detected in the probe following administration of amitriptyline. When administered in combination with exogenous adenosine, amitriptyline augmented recovery of adenosine in the probe. Pretreatment of rats with capsaicin augmented the ability of amitriptyline to increase adenosine levels detected in the dialysis probe; it also enhanced tissue recovery of exogenously administered adenosine. In uptake studies using cultured rat C6 glioma cells, amitriptyline inhibited adenosine uptake by an adenosine transporter (IC50 0.37 +/- 0.12 mM). In enzyme assays, amitriptyline had no effect on adenosine kinase or adenosine deaminase activity. These results demonstrate that amitriptyline: (a) enhances extracellular tissue levels of adenosine in the rat hindpaw following local administration in vivo and (b) inhibits adenosine uptake but has no effect on metabolism in vitro. Therefore, increased extracellular adenosine levels in vivo appear to result partially from extracellular conversion of nucleotide and partially from inhibition of uptake.

Adenosine↗
PubMed2005

Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study.

UNLABELLED: Twenty eight subjects with refractory, moderate to severe peripheral neuropathic pain participated in an open label prospective trial examining perceived analgesic effect, patient satisfaction, and safety of topical amitriptyline 2%/ketamine 1% cream. Outcome measures included an 11-point numerical rating scale for pain intensity (NRS-PI), a 5-point satisfaction scale, blood chemistry screen, drug and metabolite levels, urinalyses, electrocardiogram (ECG), and physical examination. Adverse events were monitored. Twenty-one subjects completed the trial. At 6 months, subjects reported an average long-term reduction in pain of 34% (standard deviation [SD] = 37%); 5 subjects (25%) achieved 50% or greater reduction in pain and 1 subject (5%) achieved 100% reduction in pain. At 12 months, the average reduction in pain was 37% (SD = 40%); 7 subjects (40%) achieved 50% or greater pain reduction. At the end of the study, 89% of subjects rated their satisfaction as 3/5 or greater and 2 subjects (10%) were pain free. Minimal adverse events were reported and there were no serious medication related adverse events. Blood levels revealed minimal systemic absorption. In conclusion, topical 2% amitriptyline/ 1% ketamine cream was associated with long-term reduction (6-12 months) in perceived pain, moderate to complete satisfaction, and was well tolerated in treatment of neuropathic pain. There was no significant systemic absorption of amitriptyline or ketamine. PERSPECTIVE: This study demonstrates that topical 2% amitriptyline/1% ketamine, given over 6-12 months, is associated with long-term perceived analgesic effectiveness in treatment of neuropathic pain. Antidepressants and ketamine both produce multiple pharmacologic effects that may contribute to peripheral analgesia; such actions include block of peripheral N-methyl-D-aspartate receptors, local anesthetic properties, and interactions with adenosine systems.

Adenosine↗
PubMed2005

Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain. METHODS: Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction. RESULTS: A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered. CONCLUSION: This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia.

Administration, Topical↗
PubMed2005

Topical analgesics in neuropathic pain.

Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, alpha-adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of novel topical analgesics for this condition.

Administration, Topical↗
PubMed2004

Amitriptyline produces multiple influences on the peripheral enhancement of nociception by P2X receptors.

Peripherally administered amitriptyline exhibits potential to be a locally active analgesic, while ATP augments peripheral nociception by interacting with P2X(3) receptors on sensory afferents. The present study examined the effects of amitriptyline on flinching and biting/licking behaviours and thermal hyperalgesia produced by alphabeta-methylene-ATP (alphabeta-MeATP), a ligand for P2X(3) receptors, following intraplantar administration into the hindpaw of rats. Coadministration of low doses of amitriptyline (up to 100 nmol) with alphabeta-MeATP augmented thermal hyperalgesia and flinching behaviours. The most active dose of amitriptyline (100 nmol) had no intrinsic effect. Augmentation of alphabeta-MeATP actions appears to be due to increased tissue levels of biogenic amines resulting from inhibition of uptake, as phentolamine (alpha(1)/alpha(2)-adrenergic receptor antagonist) and methysergide (5-hydroxytryptamine or 5-HT(1)/5-HT(2) receptor antagonist) inhibit the augmented flinching produced by alphabeta-MeATP/amitriptyline. When noradrenaline and 5-HT were coadministered with alphabeta-MeATP (both increase the effect of alphabeta-MeATP), amitriptyline had no effect on flinching produced by alphabeta-MeATP/noradrenaline but inhibited flinching produced by alphabeta-MeATP/5-HT. In the presence of low concentrations of formalin (0.5%, 1%; which also increase the effect alphabeta-MeATP), amitriptyline inhibited augmented behaviours. Higher doses of amitriptyline (300-1000 nmol) increased thermal thresholds, suppressed thermal hyperalgesia produced by alphabeta-MeATP, and inhibited flinching produced by alphabeta-MeATP. Collectively, these results indicate that amitriptyline produces complex influences on peripheral pain signaling by P2X receptors. Lower doses augment nociception by alphabeta-MeATP (probably by inhibiting noradrenaline and 5-HT uptake) but inhibit alphabeta-MeATP responses in the presence of inflammatory mediators (perhaps reflecting receptor blocking properties); higher doses uniformly inhibit nociception by alphabeta-MeATP (perhaps reflecting local anesthetic properties).

Adenosine Triphosphate↗
PubMed2004

Intrathecal but not intravenous opioids release adenosine from the spinal cord.

UNLABELLED: Opioids increase spinal release of adenosine in rats, and analgesia from systemic and intrathecal morphine is reduced in animals by adenosine receptor antagonists. We performed 3 studies to determine whether opioid administration also induces adenosine release in humans. To determine the effect of intrathecal opioid exposure, 15 women received intrathecal fentanyl, 50 microg, or saline, and cerebrospinal fluid was sampled at 2-minute intervals for 6 minutes before surgery. In a second study, 8 healthy volunteers received intrathecal morphine, 50 microg, plus fentanyl, 50 microg, with cerebrospinal fluid sampled 20 and 60 minutes later. To determine the effect of intravenous opioid exposure, 9 healthy volunteers received intravenous remifentanil for 60 minutes, and cerebrospinal fluid was sampled before and at the end of the infusion. Adenosine concentrations were similar in the 3 studies before opioid administration. Intrathecal fentanyl or saline did not affect adenosine concentrations during the 6 minutes in the first study. Adenosine concentrations increased significantly 20 and 60 minutes after intrathecal morphine plus fentanyl was administered. In contrast, adenosine concentrations were unaffected by intravenous remifentanil. These results suggest that intrathecal but not systemic opioid analgesia in humans is associated with spinal release of adenosine. PERSPECTIVE: Although the role of adenosine release in the spinal cord for opioid receptor activation in subsequent analgesia from opioids is controversial in laboratory studies, these clinical data suggest that local opioid receptor stimulation in the spinal cord of humans does release adenosine. Whether adenosine participates in analgesia from spinal opioids in humans is not known, but spinal adenosine itself is analgesic in humans, consistent with an opioid-adenosine role in analgesia.

Adenosine↗
PubMed2004

Peripheral P2X receptors and nociception: interactions with biogenic amine systems.

ATP is implicated in peripheral nociception following activation of P2X, and particularly P2X(3) receptors. The present study examined interactions between alphabeta-methylene-ATP (a P2X(3) receptor ligand) and 5-hydroxytryptamine (5-HT), noradrenaline (NA) and histamine, following local administration into the hindpaw, on spontaneous pain behaviors and thermal hyperalgesia in Sprague-Dawley rats. The interaction with NA was further explored using systemic 6-hydroxydopamine (6-OHDA) and locally administered indomethacin. alphabeta-methylene-ATP produced no spontaneous pain behaviors. Coadministration of 5-HT with alphabeta-methylene-ATP mildly augmented flinching behaviors, while histamine had no such effect. Coadministration of NA with alphabeta-methylene-ATP produced a pronounced expression of flinching and biting/licking behaviors. alphabeta-Methylene-ATP, given alone, produced thermal hyperalgesia, and this was markedly augmented by both 5-HT and NA, but not histamine. 6-OHDA (neurotoxin for sympathetic neurons) and indomethacin (cyclooxygenase inhibitor) reduced the augmenting effect of NA on alphabeta-methylene-ATP-induced thermal hyperalgesia, but had no effect on spontaneous pain behaviors produced by the alphabeta-methylene-ATP/NA combination. Effects of alphabeta-methylene-ATP, NA and their combination were also examined in Long Evans and Wistar rats. In both strains, alphabeta-methylene-ATP and NA both individually led to significant intrinsic flinching behaviors, and the effect of their combination was even more pronounced than in Sprague-Dawley rats. These results provide evidence for: (a) a strong enhancement by NA and 5-HT of nociception produced by peripheral P2X receptors in Sprague-Dawley rats, (b) an indirect action of NA, via sympathetic efferents and prostanoids, with thermal hyperalgesia, and (c) a greater expression of spontaneous pain behaviors with alphabeta-methylene-ATP and NA alone, and with their combination, in Wistar and Long Evans rats compared to Sprague-Dawley rats.

Adenosine Triphosphate↗
PubMed2003

Adenosine in the spinal cord and periphery: release and regulation of pain.

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.

Adenosine↗
PubMed2003

Peripheral interactions between dextromethorphan, ketamine and amitriptyline on formalin-evoked behaviors and paw edema in rats.

The local, peripheral administration of antidepressants and excitatory amino acid receptor antagonists can cause analgesia in a number of conditions. The present study examined the effects of combinations of dextromethorphan and ketamine, two clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic effect. Combination of an inactive dose of dextromethorphan with amitriptyline, and vice versa, resulted in an increase of analgesia so that previously inactive doses now caused significant analgesia. Combinations of multiple doses of ketamine with amitriptyline did not modify the response to amitriptyline. Both dextromethorphan and ketamine increased the paw edema induced by formalin, and this was blocked by low doses of amitriptyline. In the absence of formalin, amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in this study exerts multiple pharmacological effects. Increased analgesia by drug combinations (amitriptyline/dextromethorphan) could show the involvement of a number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium channels, blockage of biogenic amine receptors), while a lack of intensification (amitriptyline/ketamine) could reflect occluded actions due to expression of similar actions by the other drug. Paw edema induced by dextromethorphan and ketamine involves inhibition of biogenic amine reuptake, and the ability of amitriptyline to block biogenic amine receptors likely accounts for its inhibiton of these actions. Combinations of these particular agents could represent a method for augmented analgesia and minimization of local adverse reactions.

Amitriptyline↗
PubMed2003

Intravenous adenosine alleviates neuropathic pain: a double blind placebo controlled crossover trial using an enriched enrolment design.

Adenosine analogs produce analgesic actions in nociceptive paradigms and alleviate manifestations of neuropathic pain in nerve injury models in rodents. In humans, previous work indicates an analgesic effect for adenosine administered intravenously in postoperative and neuropathic pain. In this double blind placebo controlled crossover trial, we used an enriched enrolment design to determine the effects of intravenous adenosine (50 microg/kg/min over 60min) on neuropathic pain. In Phase 1 of the trial, adenosine was administered in an open label manner, while in Phase 2 adenosine was administered in a double blind placebo controlled manner to 23 adenosine responders who had experienced a 30% or greater response in the open trial. Outcome measures included the McGill pain questionnaire (MPQ), which generates a pain rating index (PRI), and contains a visual analog scale (VAS) of pain intensity, the neuropathy pain scale (NPS), and a VAS for pain relief. Subjects also graded the degree of allodynia and hyperalgesia using a VAS. Adenosine led to a significant reduction in spontaneous pain according to the MPQ-PRI, the MPQ-VAS and the VAS for pain relief. The NPS showed a pattern similar to the MPQ-PRI, with statistically significant reductions in scales 1 (intensity), 3 (hot), 6 (sensitive), 7 (itchy) and 9 (unpleasant). Adenosine also led to a significant reduction in pinprick hyperalgesia, but not in allodynia. Three patients from Phase 1 of the trial experienced long term resolution of their pain following intravenous adenosine (5,16,25 months). The results of this study support previous reports that indicate intravenous adenosine alleviates neuropathic pain and hyperalgesia.

Adenosine↗
PubMed2003

Topical and peripherally acting analgesics.

Acute nociceptive, inflammatory, and neuropathic pain all depend to some degree on the peripheral activation of primary sensory afferent neurons. The localized peripheral administration of drugs, such as by topical application, can potentially optimize drug concentrations at the site of origin of the pain, while leading to lower systemic levels and fewer adverse systemic effects, fewer drug interactions, and no need to titrate doses into a therapeutic range compared with systemic administration. Primary sensory afferent neurons can be activated by a range of inflammatory mediators such as prostanoids, bradykinin, ATP, histamine, and serotonin, and inhibiting their actions represents a strategy for the development of analgesics. Peripheral nerve endings also express a variety of inhibitory neuroreceptors such as opioid, alpha-adrenergic, cholinergic, adenosine and cannabinoid receptors, and agonists for these receptors also represent viable targets for drug development. At present, topical and other forms of peripheral administration of nonsteroidal anti-inflammatory drugs, opioids, capsaicin, local anesthetics, and alpha-adrenoceptor agonists are being used in a variety of clinical states. There also are some clinical data on the use of topical antidepressants and glutamate receptor antagonists. There are preclinical data supporting the potential for development of local formulations of adenosine agonists, cannabinoid agonists, cholinergic ligands, cytokine antagonists, bradykinin antagonists, ATP antagonists, biogenic amine antagonists, neuropeptide antagonists, and agents that alter the availability of nerve growth factor. Given that activation of sensory neurons involves multiple mediators, combinations of agents targeting different mechanisms may be particularly useful. Topical analgesics represent a promising area for future drug development.

Administration, Topical↗
PubMed2003

Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat.

UNLABELLED: In this study, we examined antihyperalgesic and analgesic actions after local peripheral administration of ketamine and amitriptyline in a rat model of mild thermal injury. Exposure of the hindpaw to 52 degrees C for 45 s under anesthesia produced a subsequent thermal hyperalgesia lasting at least 2 h. The local peripheral administration of ketamine (100-1000 nmol) 15 min before the thermal injury produced an antihyperalgesic effect when injected into the ipsilateral paw, whereas amitriptyline produced both antihyperalgesic (300 nmol) and analgesic (1000 nmol) effects. Administered after the thermal injury, ketamine had no effect, whereas amitriptyline retained its analgesic but not its antihyperalgesic effect. Amitriptyline (300 and 1000 nmol) produced an analgesic action when administered into the normal nonsensitized hindpaw. Both drugs increase paw volume, particularly at larger doses; biogenic amines are not involved in the action of amitriptyline, as was shown previously for ketamine. These results indicate that (a) ketamine produces antihyperalgesia, but not analgesia, when administered locally with a mild thermal injury model; (b) amitriptyline produces both antihyperalgesia and analgesia when administered locally; and (c) the increase in paw volume produced by these drugs occurs by different mechanisms. IMPLICATIONS: This study examines the pain-relieving properties of the local peripheral administration of ketamine and amitriptyline, two drugs in current clinical use, in a thermal injury model of hyperalgesia and demonstrates both antihyperalgesic and analgesic properties. These observations provide support for their potential use as local (e.g., topical) analgesics.

Administration, Topical↗
PubMed2002

Modulation of formalin-induced behaviors and edema by local and systemic administration of dextromethorphan, memantine and ketamine.

The present study examined the effects of local peripheral and systemic administration of three clinically used excitatory amino acid receptor antagonists (dextromethorphan, memantine, ketamine) on pain behaviors and edema produced by formalin (1.5% and 5%) in rats. Peripheral administration of dextromethorphan produced a locally mediated suppression of flinching behaviors induced by 1.5% and 5% formalin, but biting/licking behaviors were not affected. Memantine and ketamine had no effect on either of these behaviors. All three agents augmented edema produced by 1.5% and 5% formalin. When administered alone, dextromethorphan, memantine and ketamine produced an intrinsic paw swelling response, and this was blocked by the biogenic amine receptor antagonists mepyramine, phentolamine, methysergide and ketanserin. Following systemic administration, all three agents suppressed biting/licking behaviors, had no effect on flinching behaviors, and suppressed paw swelling induced by 5% formalin to varying degrees. These results provide evidence for a peripherally mediated antinociceptive action of dextromethorphan in the rat formalin test, but this may not necessarily be due to block of excitatory amino acid receptors as it is not observed with memantine or ketamine. All three agents produce a peripherally mediated paw swelling, which is likely due to blockade of biogenic amine reuptake. Systemic administration of all three agents produces antinociceptive and anti-inflammatory actions that may be due to block of excitatory amino acid receptors in the spinal cord.

Animals↗
PubMed2002

Intraplantar injection of glutamate evokes peripheral adenosine release in the rat hind paw: involvement of peripheral ionotropic glutamate receptors and capsaicin-sensitive sensory afferents.

Glutamate receptors have been identified on the peripheral terminals of both primary sensory afferents and sympathetic post-ganglionic neurons, and activation of these receptors produces peripheral sensitization and enhances nociception. Adenosine is an endogenous agent that has a regulatory effect on pain. In brain and spinal cord, adenosine release can be promoted by excitatory amino acids. In the present study, we used in vivo microdialysis to determine whether glutamate also can release adenosine in peripheral tissues. Rats were anesthetized with pentobarbital and microdialysis probes were implanted into the subcutaneous tissue of the plantar aspect of the rat hind paw. Subcutaneous injection of glutamate (50 microL, 0.3-100 micromol) evoked a short-lasting adenosine release immediately following drug injection. Co-administration of either the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocipine maleate (MK-801, 1 nmol) or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline (CNQX, 10 nmol) with glutamate blocked such release, suggesting an involvement of peripheral ionotropic glutamate receptors in this response. Systemic pre-treatment with capsaicin, a neurotoxin selective for unmyelinated sensory afferents, significantly reduced glutamate-evoked peripheral adenosine release, but release was not affected by systemic pre-treatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic nerve efferents. Neither MK-801 nor CNQX blocked 5% formalin-evoked adenosine release, suggesting adenosine release by formalin is not secondary to ionotropic glutamate receptor activation. We conclude that administration of glutamate evokes peripheral adenosine release, and that peripheral ionotropic glutamate receptors on unmyelinated sensory afferents are involved in such release. The released adenosine may provide a negative feedback control on nociception.

Adenosine↗
PubMed2002

Peripheral amitriptyline suppresses formalin-induced Fos expression in the rat spinal cord.

UNLABELLED: We examined the effects of systemically, spinally, and peripherally administered amitriptyline on formalin-induced Fos immunoreactivity in the lumbar spinal cord. Formalin (2.5%), injected subcutaneously into the rat hindpaw, increased Fos immunoreactivity in laminae I-II, III-IV, and V-VI of the dorsal L5 spinal cord. Amitriptyline, administered both systemically and spinally before formalin, increased flinching and concurrently decreased biting/licking behaviors, but neither route of administration produced any statistically significant change in Fos immunoreactivity. Amitriptyline coadministered with the formalin reduced both flinching and biting/licking behaviors, and significantly reduced Fos immunoreactivity, particularly in laminae I-II. These immunohistochemical changes reflect the net behavioral effects observed after the different routes of drug administration. The profile of amitriptyline action after peripheral administration may be of clinical importance because of the potential use of antidepressants as topical analgesics. IMPLICATIONS: In the formalin test, amitriptyline produces different effects on pain behaviors after systemic, spinal administration and peripheral administration. Fos protein, an indicator of neuronal activity after noxious stimulation, is upregulated after formalin injection. We examined the effects of amitriptyline on such expression and observed a reduction in expression with peripheral administration.

Amitriptyline↗