History of the Pharmacological Society of Canada 1956-2008.

The Pharmacological Society of Canada (PSC) formed in 1956 and became a constituent society of the Canadian Federation of Biological Sciences (CFBS) in 1958. Over subsequent decades, it met annually with CFBS, matured as a society, and established an identity as the voice of pharmacology in Canada. During the 1980s, it sought a larger stage and bid for, and then hosted, the XIIth International Congress of Pharmacology in Montreal in 1994. The society then participated in several joint meetings with other national pharmacology societies. In 2008, the PSC merged with the Canadian Society for Clinical Pharmacology to form the Canadian Society for Pharmacology and Therapeutics. The following article is a history of the PSC from its formation in the mid-1950s to amalgamation in 2008.

Topical and peripheral ketamine as an analgesic.

Ketamine, in subanesthetic doses, produces systemic analgesia in chronic pain settings, an action largely attributed to block of N-methyl-D-aspartate receptors in the spinal cord and inhibition of central sensitization processes. N-methyl-D-aspartate receptors also are located peripherally on sensory afferent nerve endings, and this provided the initial impetus for exploring peripheral applications of ketamine. Ketamine also produces several other pharmacological actions (block of ion channels and receptors, modulation of transporters, anti-inflammatory effects), and while these may require higher concentrations, after topical (e.g., as gels, creams) and peripheral application (e.g., localized injections), local tissue concentrations are higher than those after systemic administration and can engage lower affinity mechanisms. Peripheral administration of ketamine by localized injection produced some alterations in sensory thresholds in experimental trials in volunteers and in complex regional pain syndrome subjects in experimental settings, but many variables were unaltered. There are several case reports of analgesia after topical application of ketamine given alone in neuropathic pain, but controlled trials have not confirmed such effects. A combination of topical ketamine with several other agents produced pain relief in case, and case series, reports with response rates of 40% to 75% in retrospective analyses. In controlled trials of neuropathic pain with topical ketamine combinations, there were improvements in some outcomes, but optimal dosing and drug combinations were not clear. Given orally (as a gargle, throat swab, localized peritonsillar injections), ketamine produced significant oral/throat analgesia in controlled trials in postoperative settings. Topical analgesics are likely more effective in particular conditions (patient factors, disease factors), and future trials of topical ketamine should include a consideration of factors that could predispose to favorable outcomes.

Pain catastrophizing predicts poor response to topical analgesics in patients with neuropathic pain.

BACKGROUND: Previous research suggests that high levels of pain catastrophizing might predict poorer response to pharmacological interventions for neuropathic pain. OBJECTIVE: The present study sought to examine the clinical relevance of the relation between catastrophizing and analgesic response in individuals with neuropathic pain. Clinically meaningful reductions were defined in terms of the magnitude of reductions in pain through the course of treatment, and in terms of the number of patients whose end-of-treatment pain ratings were below 4/10. METHODS: Patients (n=82) with neuropathic pain conditions completed a measure of pain catastrophizing at the beginning of a three-week trial examining the efficacy of topical analgesics for neuropathic pain. RESULTS: Consistent with previous research, high scores on the measure of pain catastrophizing prospectively predicted poorer response to treatment. Fewer catastrophizers than noncatastrophizers showed moderate (≥ 2 points) or substantial reductions in pain ratings through the course of treatment. Fewer catastrophizers than noncatastrophizers achieved end-of-treatment pain ratings below 4/10. CONCLUSIONS: The results of the present study suggest that the development of brief interventions specifically targeting catastrophic thinking might be useful for enhancing the effects of pharmacological interventions for neuropathic pain. Furthermore, failure to account for the level of catastrophizing might contribute to null findings in clinical trials of analgesic medication.

Methylxanthines and pain.

Caffeine, an antagonist of adenosine A(1), A(2A) and A(2B) receptors, is known as an adjuvant analgesic in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in humans. In preclinical studies, caffeine produces intrinsic antinociceptive effects in several rodent models, and augments the actions of NSAIDs and acetaminophen. Antagonism of adenosine A(2A) and A(2B) receptors, as well as inhibition of cyclooxygenase activity at some sites, may explain intrinsic antinociceptive and adjuvant actions. When combined with morphine, caffeine can augment, inhibit or have no effect depending on the dose, route of administration, nociceptive test and species; inhibition reflects spinal inhibition of adenosine A(1) receptors, while augmentation may reflect the intrinsic effects noted above. Low doses of caffeine given systemically inhibit antinociception by several analgesics (acetaminophen, amitriptyline, oxcarbazepine, cizolirtine), probably reflecting block of a component of action involving adenosine A(1) receptors. Clinical studies have demonstrated adjuvant analgesia, as well as some intrinsic analgesia, in the treatment of headache conditions, but not in the treatment of postoperative pain. Caffeine clearly exhibits complex effects on pain transmission; knowledge of such effects is important for understanding adjuvant analgesia as well as considering situations in which dietary caffeine intake may have an impact on analgesic regimens.

Observational Study of Qigong as a Complementary Self-Care Practice at a Tertiary-Care Pain Management Unit.

Qigong, which can be characterized in many different ways, is offered as a complementary self-care practice at a tertiary-care pain management unit in Halifax, Nova Scotia. This report provides a quantitative and qualitative assessment of two groups engaged in qigong practice in this context as part of two Research in Medicine (RIM) projects (2014-15, 2016-17). It includes assessments of pain, mood, quality of life, sleep, and fatigue, considers outcomes in relation to the amount of practice, and considers whether health attitudes would help determine who might benefit from the practice. There were 43 participants (28 ongoing practitioners, 15 new to qigong). The ongoing practice group in RIM2 had significant benefits over time in pain, mood, quality of life, and fatigue in quantitative scores, but changes were not significant in RIM 1. There were no differences in any measures in those new to qigong. Qualitative comments in core and other domains reflected good or better outcomes in 16 subjects in the ongoing group who practiced consistently. In those who practiced less, results were more variable. In most of those new to qigong, the practice was limited and comments indicate minimal changes. Those engaged in qigong have a stronger internal health locus of control than control subjects. Diligent qigong practice provides multiple health benefits for those with chronic pain, and qualitative assessments are essential for documenting these effects. For those new to qigong, factors needed to effectively engage practice need to be explored further to optimize program delivery. The trial is registered with http://www.clinicaltrials.gov (NCT04279639).

A qualitative systematic review of head-to-head randomized controlled trials of oral analgesics in neuropathic pain.

BACKGROUND: Neuropathic pain (NP) encompasses many difficult-to-treat disorders. There are few head-to-head, comparative, randomized controlled trials (RCTs) of drugs for NP in different analgesic categories, or of different drugs within a category, despite many placebo-controlled RCTs for individual agents. Well-designed head-to-head comparative trials are an effective way to determine the relative efficacy and safety of a new drug. OBJECTIVE: To perform a systematic review of head-to-head RCTs of oral analgesics in NP. METHODS: A systematic review of RCTs involving NP patients was performed, of which head-to-head comparative trials were selected. Reference lists from published systematic reviews were searched. These studies were rated according to the Jadad scale for quality. RESULTS AND CONCLUSIONS: Twenty-seven such trials were identified. Seventeen were comparisons of different analgesics, and 10 were of different drugs within an analgesic class. Important information was obtained about the relative efficacy and safety of drugs in different categories and within a category. Some significant differences between active treatments were reported. Trial inadequacies were identified. More and improved head-to-head RCTs are needed to inform clinical choices.

Adrenergic regulation of P2X3 and TRPV1 receptors: differential effects of spared nerve injury.

Local application of alphabetaMeATP (ligand for P2X3 receptors) and capsaicin (ligand for TRPV1 receptors) to the rat hindpaw produces pain behaviors (flinching) which are enhanced by noradrenaline (NA). In this study, we have examined the effect of nerve injury on adrenergic regulation of P2X3 and TRPV1 receptors by administering alphabetaMeATP and capsaicin, alone and in combination with NA, into the lateral and medial hindpaw in the spared nerve injury (SNI) model; this allows for an exploration of the role of injured and uninjured afferents in their effects on nociceptive signaling using a behavioral model. Following lateral hindpaw injections (sural sensory field), effects of NA and alphabetaMeATP, both alone and in combination, were increased following SNI, but no such effects were seen following medial hindpaw injections (saphenous sensory field). Following lateral hindpaw injections, the effect of capsaicin alone was unaltered following SNI, but the effect of NA/capsaicin was reduced; this latter effect was not seen following medial hindpaw injections. At the lateral site, prazosin (alpha1-adrenergic receptor antagonist) inhibited the effect of NA/alphabetaMeATP following SNI, but neither prazosin nor GF109203X (protein kinase C inhibitor) inhibited the effect of NA/capsaicin following SNI. These results demonstrate: (a) an enhanced adrenergic regulation of P2X3 receptor activity at lateral sites following SNI where signaling afferents are directly influenced by injured neurons; (b) differential effects on adrenergic regulation of TRPV1 receptors under the same conditions; (c) lack of such changes when agents are administered into medial sites following SNI.

Caffeine reverses antinociception by amitriptyline in wild type mice but not in those lacking adenosine A1 receptors.

Amitriptyline is used to treat neuropathic pain in humans. It produces antinociception in several animal models of pain, and this effect is blocked by methylxanthine adenosine receptor antagonists which implicates adenosine it its actions. Here, the antinociceptive effect of amitriptyline, and the ability of caffeine to reverse it, were examined using the formalin test (a model of persistent pain) in wild type mice and mice lacking the adenosine A(1) receptor (A1R). Amitriptyline produced dose-related suppression of flinching in wild type mice following both systemic and intraplantar drug administration; both of these effects were unaltered in A1R -/- mice. Following systemic administration, caffeine reversed the systemic effect of amitriptyline in wild type, but not A1R -/- mice; -/+ mice exhibited an intermediate effect. Intraplantar administration of caffeine also reversed the effect of intraplantar amitriptyline in A1R +/+, but not in -/- or +/- mice. These results indicate that adenosine A(1) receptors are not required in order for amitriptyline to cause antinociception in mice, but they are required to see caffeine reversal of this antinociceptive effect. When A1Rs are present, actions of amitriptyline may, however, partly depend on A1Rs.

Alpha1-adrenergic receptors augment P2X3 receptor-mediated nociceptive responses in the uninjured state.

UNLABELLED: In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X(3) receptor-mediated nociceptive responses on sensory nerve endings was examined by using selective AR receptor agonists and antagonists in Sprague Dawley rats in the uninjured state. Local administration of alphabeta-methyleneATP (ligand for P2X3/P2X2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (alpha1- and alpha2-AR agonist) and phenylephrine (alpha1-AR agonist) but not clonidine or UK 14,304 (alpha2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/alphabeta-methyleneATP was suppressed by low doses of prazosin (alpha1-AR antagonist), and this reduction was selective compared with yohimbine (alpha2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/alphabeta-methyleneATP. Using thermal threshold determinations, adrenaline and phenylephrine but not clonidine or UK 14,304, mimicked the action of NA in augmenting reductions in thermal thresholds produced by alphabeta-methyleneATP. Terazosin (another alpha1-AR antagonist) inhibited hyperalgesia produced by NA/alphabeta-methyleneATP. These results provide evidence for alpha1-AR involvement in adrenergic augmentation of P2X3/P2X2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats. PERSPECTIVE: This study indicates the alpha1-adrenergic receptor subtype mediates adrenergic augmentation of the activation of sensory nerves by purinergic P2X3 receptors (respond to ATP) in the periphery. Observations are potentially relevant to chronic pain conditions in which sympathetic nerves influence sensory nerves.

Qigong and Fibromyalgia circa 2017.

Qigong is an internal art practice with a long history in China. It is currently characterized as meditative movement (or as movement-based embodied contemplative practice), but is also considered as complementary and alternative exercise or mind-body therapy. There are now six controlled trials and nine other reports on the effects of qigong in fibromyalgia. Outcomes are related to amount of practice so it is important to consider this factor in overview analyses. If one considers the 4 trials (201 subjects) that involve diligent practice (30-45 min daily, 6-8 weeks), there are consistent benefits in pain, sleep, impact, and physical and mental function following the regimen, with benefits maintained at 4-6 months. Effect sizes are consistently in the large range. There are also reports of even more extensive practice of qigong for 1-3 years, even up to a decade, indicating marked benefits in other health areas beyond core domains for fibromyalgia. While the latter reports involve a limited number of subjects and represent a self-selected population, the marked health benefits that occur are noteworthy. Qigong merits further study as a complementary practice for those with fibromyalgia. Current treatment guidelines do not consider amount of practice, and usually make indeterminate recommendations.

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.

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.

Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain.

INTRODUCTION: Neuropathic pain (NP) has several therapeutic options but efficacy is limited and adverse effects occur, such that additional treatment options are needed. A topical formulation containing amitriptyline 4% and ketamine 2% (AmiKet) may provide such an option. AREAS COVERED: This report summarizes both published and unpublished results of clinical trials with AmiKet. In post-herpetic neuralgia (PHN), AmiKet produces a significant analgesia which is comparable to that produced by oral gabapentin. In diabetic painful neuropathy, AmiKet showed a strong trend towards pain reduction. In mixed neuropathic pain, case series reports suggest a favourable response rate, but are limited by trial characteristics. AmiKet is absorbed minimally following topical administration. Over 700 patients have now received topical AmiKet in clinical regimens, and it is well-tolerated with the adverse effects mainly being application site reactions. Both agents are polymodal, and several mechanisms may contribute to the peripheral efficacy of AmiKet. EXPERT OPINION: Topical AmiKet has the potential to be a first-line treatment option for PHN, and to be useful in other NP conditions. Furthermore, AmiKet has the potential to be an adjunct to systemic therapies, with the targeting of a peripheral compartment in addition to central sites of action representing a rational drug combination.

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.

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.

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 A1 receptor-dependent antinociception induced by inosine in mice: pharmacological, genetic and biochemical aspects.

Inosine is an endogenous nucleoside that has anti-inflammatory and antinociceptive properties. Inosine is a metabolite of adenosine, and some of its actions suggest the involvement of adenosine A1 receptors (A1Rs). The purpose of this study was to better understand mechanisms of inosine-induced antinociception by investigating the role of A1Rs and purine metabolism inhibitors. Inosine antinociception was evaluated using the formalin test in mice. An A1R-selective antagonist (DPCPX), A1R knockout mice (gene deletion) and mice with A1R reduced expression (antisense oligonucleotides) were used to assess the role of A1Rs in the antinociceptive action of inosine. Binding assays were performed to compare the affinity of inosine and adenosine for A1Rs. Finally, the role of adenosine and inosine breakdown was assessed using deoxycoformycin (DCF) and forodesine (FDS) as enzymatic inhibitors of adenosine deaminase and purine nucleoside phosphorylase, respectively. Inosine induced antinociception in the formalin test when given by systemic, spinal and peripheral routes. Systemically, inosine exhibited a potency similar to adenosine, and its effects were inhibited by DPCPX. Inosine did not induce antinociception in A1R knockout mice or in mice with reduced A1R expression. In binding studies, inosine bound to A1Rs with an affinity similar to adenosine. DCF had no effect on inosine actions. FDS augmented the antinociceptive effect of a low systemic dose of inosine and, at a higher dose, induced antinociception by itself. Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor.

Desipramine potentiates spinal antinociception by 5-hydroxytryptamine, morphine and adenosine.

The effects of pretreatment with desipramine, a selective noradrenaline (NA) uptake blocker, on spinal antinociception by 5-hydroxytryptamine (5-HT), morphine and an adenosine analog (NECA) in the rat hot-plate test were examined to determine if endogenous NA is involved in the spinal action of these agents. Desipramine, 25 mg/kg, had no significant intrinsic effect in the hot-plate test but potentiated spinal antinociception by NA and 5-HT. Potentiation was more prominent at higher doses of NA and 5-HT. Desipramine also enhanced the action of morphine and NECA, but, in these instances, the greatest enhancement occurred at lower doses. These results, in conjunction with others, suggest that 5-HT releases NA from the spinal cord while morphine and NECA interact synergistically with endogenously released NA.

Antinociception by tricyclic antidepressants in the rat formalin test: differential effects on different behaviours following systemic and spinal administration.

The present study (1) examined analgesic effects of systemically and spinally administered antidepressants (ADs) on phase 2 flinching and biting/licking behaviours in the rat formalin test, a model considered to be of greater relevance to clinical pain than acute threshold tests, and (2) determined whether motor or anti-inflammatory effects contributed to such actions. Systemic administration of amitriptyline (3-20 mg/kg) produced a dose-related enhancement of flinching behaviours, while at the same time suppressing biting/licking behaviours. Imipramine (except for 20 mg/kg), nortriptyline, desipramine and fluoxetine had no significant effect on flinching behaviours, while producing a dose-related suppression of biting/licking behaviours. When administered spinally, either by acute lumbar puncture or via chronically implanted intrathecal cannulas, amitriptyline similarly augmented flinching behaviours. When given by lumbar puncture, amitriptyline suppressed biting/licking behaviours, but when intrathecal cannulas were used, this behaviour was not expressed in the formalin group. Other ADs also suppressed biting/licking behaviours without affecting flinching when given by lumbar puncture. Effects on paw volume were determined at the end of behavioural testing. Systemic administration of all ADs produced a dose-related reduction in paw volume. Spinal administration of nortriptyline by lumbar puncture also reduced paw volume, but for other agents, the reduction was not significant. Motor effects were noted qualitatively throughout these experiments, and considered in relation to nociceptive behaviours. These results indicate (a) a marked dissociation between the effects of systemic ADs on flinching and biting/licking behaviours in the formalin test, (b) spinal efficacy of ADs that essentially reproduces effects seen with systemic administration when given by lumbar puncture, (c) a lack of causality between anti-inflammatory effects of ADs and their analgesic properties in the formalin test, and (d) a contribution of motor effects to analgesic actions at higher doses affecting biting/licking but not flinching behaviours.

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.