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Analgesia, Vol. 6, pp. 1-2
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Copyright © 2002 Cognizant Comm. Corp.
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Differential Phosphatidylinositol Mediation of d1 and d2 Supraspinal Antinociception in Mice

Rebecca P. Martinez1 and Robert B. Raffa2

1The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477
2Temple University School of Pharmacy, Philadelphia, PA 19140

Multiple lines of evidence suggest that antinociception induced by d-opioid agonists is mediated by receptor subtypes (d1 and d2), yet only one has been cloned. It has recently been reported that LiCl significantly attenuates the spinal antinociception induced by the d2-selective agonist [D-Ala2,Glu4]deltorphin II. We report that pretreatment with LiCl (424 mg/kg = 10 mmol/kg, SC, 18 h prior) attenuates [D-Ala2,Glu4]deltorphin II-induced supraspinal antinociception, but not that induced by the d1-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE). This finding suggests differential involvement of phosphatidylinositol second messenger pathway mediation of d-opioid receptor subtypes and possible explanation for functional differentiation in vivo.

Key words: Delta-opioid antinociception; Lithium; Phosphatidylinositol

Address correspondence and reprint requests to Robert B. Raffa, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140. Tel: (215) 707-4976; Fax: (215) 707-5228; E-mail: rraffa@nimbus.temple.edu

Analgesia, Vol. 6, pp. 3-6
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Companion Animal Analgesia: Assessment of Pain

Germaine Connolly

Anesthetics and Pain Management, Division of Therapeutic Drugs for Non-Food Animals, FDA Center for Veterinary Medicine, Hamilton, VA 20159

Animal pain models are used in laboratory studies in companion animals to test the effectiveness of various analgesics used to control acute and chronic pain in those species. On the other hand, clinical field trials evaluate short-term perioperative pain or long-term osteoarthritic pain in client-owned animals. Because commonly performed surgical procedures in the clinical setting provide a source for the evaluation of analgesics in animals receiving similar levels of nociceptive stimuli, they are described as pain models within the context of this article. Similarly, common chronic conditions resulting in consistent and demonstrable levels of pain (e.g., osteoarthritis of the canine hip joint) are also defined as clinical models of pain. Veterinarians and pet owners want to avoid causing pain to animals in their care. One way of reducing pain is to administer safe and effective analgesics. Pain assessment models are used to measure the effectiveness of an analgesic. FDA approval decisions are based on data obtained from some pain assessment models. Many steps are taken to avoid inducing unnecessary pain in the use of these models. Information contained in this article briefly discusses the ethics of using pain models in animals, also describing laboratory and clinical pain models for acute pain as used in companion animals (dogs, cats, and horses). Methods of pain assessment are listed as well as behavioral criteria used for the evaluation of analgesic effectiveness. The article ends with a discussion of subjective and objective lameness assessment for the evaluation of chronic pain.
Conclusion: Many pain models exist but none are applicable to all conditions of animal pain and subjective assessment of pain still incorporates a potentially inappropriate human perspective.

Key words: Animal pain models; Pain assessment; Analgesic effectiveness; Companion animals; Ethical considerations

Address correspondence and reprint requests to Germaine Connolly, DVM, Anesthetics and Pain Management, Division of Therapeutic Drugs for Non-Food Animals, FDA Center for Veterinary Medicine, P.O. Box 547, Hamilton, VA 20159. Tel: (540) 338-5556; Fax: (301) 827-2240; E-mail: gconnoll@cvm.fda.gov

Analgesia, Vol. 6, pp. 7-10
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Copyright © 2002 Cognizant Comm. Corp.
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Modulation of Morphine Analgesia by a Nitric Oxide Synthase Inhibitor Microinjected Into the Periaqueductal Gray in Rats

Khalid Benamar, Li Xin, Ellen B. Geller, and Martin W. Adler

Center for Substance Abuse Research and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA

This study evaluated the effect on morphine-induced antinociception of administration of an inhibitor of nitric oxide synthase, N-nitro-L-arginine methyl ester (L-NAME), into the periaqueductal gray (PAG) of rats. Rats were microinjected with L-NAME (25, 50, or 100 mg) into the PAG. Thirty minutes later, morphine (10 mg/kg) was injected SC. Antinociception was measured using the cold-water (-3°C) tail-flick test. L-NAME potentiated the effect and prolonged the duration of action of morphine. However, none of the doses of L-NAME itself given into PAG had any effect on tail-flick latencies during the 240-min recording period. The data suggest that nitric oxide (NO) in the PAG is involved in the modulation of morphine-induced antinociception.

Key words: Antinociception; Morphine; Periaqueductal gray; Nitric oxide; N-Nitro-L-arginine methyl ester

Address correspondence and reprint requests to Khalid Benamar, Ph.D., Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140. Tel: (215) 707-5305; Fax: (215) 707-1904; E-mail: kbenamar@hotmail.com

Analgesia, Vol. 6, pp. 11-18
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Thalidomide Blockade of Lipopolysaccharide- and Lithium Chloride-Induced Hyperalgesias

Eric P. Wiertelak, Dee M. Koski, Jason Carriere, Shane Stamschror, and Shannon Robins

Department of Psychology, Macalester College, St. Paul, MN 55105

The IP injection of lithium chloride (LiCl) or lipopolysaccharide (LPS) induces an "illness-induced" centrally mediated hyperalgesic state. Illness-induced hyperalgesia relies on the immune system in several ways, as IP injection of interleukin-1b (IL-1b) or tumor necrosis factor (TNF) induces the effect, while IL-1b or TNF antagonism blocks this hyperalgesia. As this hyperalgesia has been shown to result from activation of hepatic vagal afferents by these cytokines, the present studies employed thalidomide as an immunomodulatory drug, to further examine the local immune activation in illness-induced hyperalgesia and the development of the cytokine response that ultimately leads to hyperalgesia. In three separate experiments, the effect of thalidomide was assessed versus controls on LPS- and LiCl-induced hyperalgesias in the tail flick test, and LPS-induced hyperalgesia as measured by the formalin test. In the tail flick test, thalidomide reversed the illness-induced hyperalgesias induced by IP LPS or LiCl to an apparent analgesic state. In the formalin test, thalidomide blocked the hyperalgesia induced by IP LPS, but did not result in analgesia. These experiments provide evidence that thalidomide has the ability to alter the centrally mediated increase in pain sensitivity that is normally seen in LPS and LiCl illness-induced hyperalgesia paradigms. These results support the contention that thalidomide can act via its immunomodulatory effects as a novel antihyperalgesic agent and provide further evidence that LiCl- and LPS-induced hyperalgesias result from TNF and IL-1b activity.

Key words: Thalidomide; Hyperalgesia; Lithium chloride; Lipopolysaccharide

Address correspondence and reprint requests to Eric P. Wiertelak, Department of Psychology, Macalester College, 1600 Grand Avenue, Saint Paul, MN 55105. Tel: (651) 696-6111; Fax: (651) 696-6348; E-mail: iertelak@macalester.edu

Analgesia, Vol. 6, pp. 19-25
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Copyright © 2002 Cognizant Comm. Corp.
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192 IgG-Saporin-Induced Selective Cholinergic Denervation Modifies Formalin Pain in Male Rats

Anna Maria Aloisi, Ilaria Ceccarelli, Katiuscia Cavallaro, and Andrea Scaramuzzino

Institute of Human Physiology, University of Siena, 53100 Siena, Italy

Previous studies showed an involvement of ACh in pain processes. The aim of the present experiment was to investigate the role of central cholinergic pathways in formalin pain-induced responses. 192 IgG-saporin, a potent immunotoxin able to induce the loss of cholinergic neurons, was ICV injected into male rats for 3 consecutive days; vehicle was used as control. During the 3 weeks following treatment (saporin or vehicle), the pain threshold (plantar test) and spontaneous behaviors (hole board) were determined, then the animals were subjected to the formalin test (50 ml, 5% SC in the dorsal hind paw). The formalin-evoked licking, flexing, and jerking of the injected paw were recorded for 60 min. No differences between groups were found in the plantar test and hole board determinations. None of the formalin-evoked responses showed a saporin-induced modification during the first 15 min (first phase). During the second phase (15-60 min), there was a difference in the first part (ascending) of the curve, with higher levels of licking and jerking in the saporin-treated animals than in controls, and in the second part (descending), with lower levels of licking and jerking in saporin-injected animals. The results show an involvement of the cholinergic system in the second, longer lasting phase of formalin pain. The cholinergic activation, known to be induced by pain mostly during the second phase, appears to delay the behavioral output due to the central processes involved in the maintenance of pain.

Key words: ACh; Pain; Behavior; Plantar test; Rat

Address correspondence and reprint requests to Dr. Anna Maria Aloisi, Istituto di Fisiologia Umana, Via Aldo Moro, 53100 Siena, Italy. Tel: +39 0577234103; Fax: +39 0577234037; E-mail: Aloisi@unisi.it

Analgesia, Vol. 6, pp. 27-37
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Copyright © 2002 Cognizant Comm. Corp.
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Participation of the Nitric Oxide-cGMP Pathway in the Peripheral Antinociceptive Effect of Nimesulide

Naveen K. Jain,1 C. S. Patil,2 Shrinivas K. Kulkarni,1 and Amarjit Singh2

1Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India
2R&D Division, Panacea Biotec Ltd., P.O. Lalru, Chandigarh Road, Punjab-140 501, India

Background: Nitric oxide (NO) is a free radical that plays an important role in many physiological and pathological processes. Evidence suggests that NO-cGMP signaling pathway participates in the nociceptive mechanism.
Purpose: The present study was aimed to explore the role of NO-cGMP pathway in nimesulide-induced antinociception in experimental animals.
Methods: Both peripheral (acetic acid-induced chemonociception or carrageenan-induced hyperalgesia) and central nociception (tail flick or hot plate methods) were used.
Results: Nimesulide exhibited dose-dependent (1, 2, 5, and 10 mg/kg, p.o.) antinociception against acetic acid-induced writhing and tail flick or hot plate assays in mice. Local administration of nimesulide (25-50 mg/paw, i.pl.) also attenuated carrageenan-induced hyperalgesia. In peripheral nociceptive reaction (acetic acid-induced chemonociception), the antinociceptive effect of nimesulide (2 mg/kg, p.o.) was enhanced by coadministration of sodium nitroprusside (0.25 mg/kg, i.p.), a nitric oxide donor, and L-arginine (50 mg/kg, i.p.), a nitric oxide synthase precursor. Nimesulide-induced analgesia was significantly blocked by methylene blue (1 mg/kg, i.p.), a guanlylate cyclase inhibitor, and L-NAME (10 mg/kg, i.p.), a nitric oxide synthase inhibitor. Both these agents also reversed the facilitatory effect of L-arginine (50 mg/kg, i.p.) and sodium nitroprusside (0.25 mg/kg, i.p.) on nimesulide analgesia. Furthermore, methylene blue (100 mg/paw, i.pl.) also blocked the nimesulide-induced local effect. L-NAME (10 mg/kg, i.p.) and methylene blue (1 mg/kg, i.p.), however, failed to reverse the nimesulide-induced antinociception in tail flick or hot plate assay.
Conclusion: These results suggest that, besides the inhibitory action on prostaglandin synthesis, the activation of the NO-cGMP pathway plays an important role in the peripheral antinociceptive action of nimesulide.

Key words: Nimesulide; Antinociception; Nitric oxide; cGMP; L-NAME

Address correspondence and reprint requests to Prof. Shrinivas K. Kulkarni, Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India. Fax: +91-0172 779426, 541409; E-mail: skpu@yahoo.com

Analgesia, Vol. 6, pp. 39-42
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Copyright © 2002 Cognizant Comm. Corp.
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The Levels of Tramadol and its M1 Metabolite in the Plasma, Cerebrospinal Fluid, and Midbrain Following Acute Tramadol Administration in Rats*

Mauro Bianchi, Paolo Ferrario, and Alberto E. Panerai

Department of Pharmacology, University of Milan, 20129 Milano, Italy

Background: Tramadol is a central acting analgesic drug that exerts its effects by activating opioid receptors and enhancing neuronal monoamine synaptic concentration. There is growing evidence that O-desmethyl-tramadol (M1), the active metabolite of tramadol, induces potent antinociception and is largely responsible for its opioid effects. However, the central levels of M1 after peripheral tramadol administration have never been measured with precision.
Purpose: To evaluate simultaneously tramadol and M1 metabolite concentrations in plasma, cerebrospinal fluid (CSF), and midbrain after the acute injection of an antinociceptive dose of tramadol in rats.
Methods: Male Sprague-Dawley CD rats were used. Tramadol was administered at the dose of 10 mg/kg IP. Samples of blood, CSF, and the midbrain were collected 30, 60, and 120 min after tramadol injection. Tramadol and M1 concentrations were measured by high performance liquid chromatography (HPLC) with UV detection.
Results: The plasma concentrations of tramadol and M1 were similar at 30, 60, and 120 min after treatment. At both 30 and 60 min after tramadol injection, the CSF concentration of M1 was higher than that of tramadol. The midbrain concentrations of M1 were lower than those of tramadol after 30 min and similar to those of tramadol at 60 and 120 min after injection.
Conclusions: The findings of this study show that, after tramadol peripheral injection, the active metabolite M1 reaches significant concentrations in the central nervous system. These results suggest that M1 strongly contributes to the antinociceptive effect induced by tramadol in rats.

Key words: Tramadol; M1 metabolite; Rat plasma; Central nervous system

Address correspondence and reprint requests to Mauro Bianchi, M.D., Department of Pharmacology, Via Vanvitelli, 32, 20129 Milano, Italy. Tel: 39-2-58356930; Fax: 39-2-58356933; E-mail: mauro.bianchi@unimi.it

*A preliminary report of the data reported here was presented at the Third Congress of the European Federation of IASP Chapters (Nice, France, September 2000).

Analgesia, Vol. 6, pp. 43-45
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Copyright © 2002 Cognizant Comm. Corp.
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Adenosine - a New Local Analgesic Agent? Pharmacological Aspects and Preliminary Clinical Experience in Caudal Blockade

Oto Masar1 and Silvester Kremery2

1Department of Anesthesiology and Intensive Care, County Hospital, 901 22 Malacky, Slovak Republic
2Department of Geriatric Medicine, Comenius University Faculty of Medicine, Dumbierska 3, 831 01 Bratislava, Slovak Republic

Background and Purpose: Authors review caudal blockade by administering various pharmacological agents via hiatus sacralis, and thus induce epidural anesthesia, or analgesia. The present study evaluated the benefits and potential risks of adenosine in combination with local anesthetics (bupivacaine) and opioids (tramadol) in patients undergoing blockade. The most frequent indications for caudal blockade are: hernia of intervertebral disc, spinal stenosis, and intervertebral osteochondrosis and spondyloarthrosis.
Patient Characteristics and Methods: There were 40 patients with severe radicular irritation due to hernia of intervertebral disc (CT verification) indicated for caudal blockade. All patients suffered from severe pain and acute lumboischiadic syndrome. Caudal blockade was performed daily for 5 consecutive days. Adenosine (3 mg) was administered in combination with 20 ml 0.125% bupivacaine (group A). In group B patients, 100 mg of tramadol was added to the combination used for group A. Adequacy of analgesia was assessed according to visual analogue scale (1-10) and 4-grade verbal rating scale (VRS) after the end of treatments.
Conclusions: Our results confirmed good analgesic activity and tolerance of locally administered adenosine. Induced antinociception lasted significantly longer in comparison with biological half-life of administered drugs. Mechanisms of adenosine-induced analgesia are not completely understood, but the dorsal horn of the spinal cord could be an interactive structure of adenosine's activity, thus influencing the central pain perception in humans. These effects are of prolonged duration and future studies should evaluate risks/benefits of adenosine receptor agonists in clinical practice.

Key words: Adenosine; Analgesia; Antinociception; Caudal blockade

Address correspondence and reprint requests to Oto Masar, M.D., Ph.D., Associate Professor and Chairman, Department of Anesthesiology and Intensive Care, County Hospital, 901 22 Malacky, Slovak Republic. Tel: +421-903 325 498; E-mail: otomasar@nextra.sk