Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats

The present study directly compared the antinociceptive and toxic effects of the neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) with (-)-nicotine and (+)-epibatidine. Like (-)-nicotine (0.8 and 1.6 mg/kg s.c.) and (+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05 and 0.1 mg/kg s.c.) increased response latencies in the hot-plate test in rats, indicating that it has antinociceptive activity. In contrast to (-)-nicotine and (+)-epibatidine, ABT-594 did not cause rotarod impairment at antinociceptive doses but did cause hypothermia and life-threatening adverse effects including seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1 and 0. 03 mg/kg i.v.) and (+)-epibatidine (0.001 and 0.003 mg/kg i.v.). Both the antinociceptive and toxic effects (convulsions and hypertension) were abolished by pretreatment with the brain penetrant neuronal nAChR antagonist mecamylamine (1 mg/kg s.c.; i.v. for cardiovascular studies), demonstrating that these actions of ABT-594 were mediated via activation of neuronal nicotinic receptors. Continuous infusion of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days followed by challenge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like abstinence syndrome suggesting that ABT-594 has nicotine-like dependence liability. These findings indicate that the acute safety profile of ABT-594 is not significantly improved over other nicotinic analgesics.     

ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED(50) = 5 micromol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED(50) = 70 micromol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at 相似文献   

Role of N-methyl-D-aspartate and opiate receptors in nociception during and after ischaemia in rats.

We have investigated the effects of systemic administration of two N-methyl-D-aspartate (NMDA) receptor antagonists and two opiate agonists on nociception during and after tail ischaemia in conscious rats. The two NMDA receptor antagonists, D-2-amino-5-phosphonovalerate (APV) and ketamine hydrochloride, did not alter tail flick latencies in rats not subjected to ischaemia but inhibited post-ischaemic hyperalgesia (PIH) in a dose-dependent manner. Neither of these agents impaired motor function of the rats, as assessed by rotarod performance, suggesting a purely sensory antinociceptive effect. The antinociceptive effect of APV during reperfusion following ischaemia was not antagonised by the mu-opiate receptor antagonist naloxone (1 mg/kg). The two opiate receptor agonists, morphine and pethidine, increased tail flick latencies in rats not subjected to ischaemia, inhibited PIH in a dose-dependent manner, and also caused significant motor malfunction, all in naloxone-reversible fashion. We conclude that the role of the NMDA receptor in mediating afferent nociceptive traffic is confined to its involvement in neuronal events mediating hyperalgesia.     

A randomized,double-blind,placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain

ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 μg BID, ABT-594 225 μg BID, or ABT-594 300 μg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0–10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, −1.1; 150 μg BID, −1.9; 225 μg BID, −1.9; 300 μg BID, −2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 μg BID, 46% for 225 μg BID, and 66% for 300 μg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.     

Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert centrally mediated antinociception in the rat cyclophosphamide cystitis model of visceral pain.

A visceral pain model incorporating use of cyclophosphamide (CP) to induce bladder inflammation has been described. CP treatment in rats produces changes in behavior (abnormal postures and eye closure) and respiration rate indicative of visceral pain. We characterized the dose-dependency and progression of CP-induced cystitis pain after intraperitoneal (i.p.) CP. The behavioral and respiration rate changes were ameliorated by systemic morphine and ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine], a neuronal nicotinic acetylcholine receptor agonist, in a manner reversible by naloxone and mecamylamine, respectively. Sites of antinociceptive actions of morphine and ABT-594 were investigated using systemic, intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of blood-brain barrier impenetrant antagonists. Naloxone methiodide produced a complete antagonism of morphine antinociception after i.c.v. but not i.p. or i.t. administration. Chlorisondamine blocked ABT-594 antinociception after i.c.v. but not i.p. administration. Further pharmacological characterization of behavioral and respiration changes in CP-cystitis was performed using standard analgesics. The alpha(2)-adrenoceptor agonist clonidine produced a weak attenuation of CP-pain behavior. NSAIDs (ibuprofen, acetaminophen, and celecoxib) and anticonvulsants (gabapentin and lamotrigine) were without effect. These results demonstrate that morphine and ABT-594 produce antinociception in CP-cystitis by a predominantly supraspinal site of action, and that mechanisms producing robust centrally-mediated antinociception could be beneficial in cystitis pain. PERSPECTIVE: In this article, potential antinociceptive effects of a variety of pharmacological agents were evaluated in a rat cystitis pain model. Morphine and a nicotinic acetylcholine receptor agonist ABT-594 were found to exert potent antinociception in this model. Findings presented here aid identification of agents to treat cystitis pain in the clinic.     

The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. (Novartic Institute for Medical Sciences, London, United Kingdom) Pain. 2001;92:91–100.

This study examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioral effects characteristic of central cannabinoid activity. WIN55, 212‐2 (0.3–10 mg/kg^?1), CP‐55, 940 (0.03–1 mg/kg^?1), and HU‐210 (0.001–0.03 mg/kg^?1) were all active in a “tetrad” of tests consisting of tail‐flick, catalepsy, rotarod, and hypothermia following subcutaneous administration, with a rank order of potency in each of HU‐210> CP‐55, 940> WIN55, 212‐2. The effects of WIN55, 212‐2 in each assay were blocked by the Cannabinoid₁ (CB₁) antagonist SR141716A. In the partial sciatic ligation model if neuropathic pain WIN55, 212‐2, CP‐55, 940, and HU‐210 produced complete reversal of mechanical hyperalgesia within 3 hours of subcutaneous administration with D₅₀ values of 0.52, 0.08, and 0.005 mg/kg^?1, respectively. In this model WIN55, 212‐2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55, 212‐2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB₁ antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55, 212‐2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into contralateral paw. The antihyperalgesic effect of WIN55, 212‐2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. Conclude that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via action in both the CNS and in the periphery. Comment by Leland Lou, M.D. Rat study that looked at the potential of cannabinoids in the management of neuropathic pain. The data seem to indicate the presence of peripheral cannabinoid receptors for suppression of neuropathic pain. Historically, a central mechanism of action for cannabinoid's analgesic and antihyperalgesic properties is thought to be responsible. Unfortunately, this report only confirms previous studies finding a peripheral mechanism of action.     

Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dose-dependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.     

Amelioration of functional,biochemical and molecular deficits by epigallocatechin gallate in experimental model of alcoholic neuropathy

Long term alcohol consumption leads to decreased nociceptive threshold characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism involved in this pain includes increased oxidative‐nitrosative stress, release of pro‐inflammatory cytokines and neuronal apoptosis. The present study was designed to explore the protective effect of epigallocatechin‐3‐gallate against alcoholic neuropathic pain in rats. Rats fed with alcohol (35%) for 10 weeks showed markedly decreased tail flick latency in tail‐immersion test (thermal hyperalgesia), vocalization threshold in Randall—Sellito test (mechanical hyperalgesia) and paw‐withdrawal threshold in von‐Frey hair test (mechanical allodynia) along with enhanced oxidative‐nitrosative stress and inflammatory mediators (TNF‐α, IL‐1β and TGF‐β1 levels). Co‐administration of epigallocatechin‐3‐gallate (25–100 mg/kg) significantly and dose‐dependently prevented functional, biochemical and molecular changes associated with alcoholic neuropathy. In conclusion, the current findings suggest the neuroprotective potential of epigallocatechin‐3‐gallate in attenuating the functional, biochemical and molecular alterations associated with alcoholic neuropathy through modulation of oxido‐inflammatory cascade.     

Antinociceptive effect of systemic gabapentin in mononeuropathic rats, depends on stimulus characteristics and level of test integration

The anticonvulsant gabapentin is effective against neuropathic pain, but the primary site(s) and mechanism(s) of action are unknown. In order to explore the relative contribution of spinal versus supra-spinal mechanisms to the antinociceptive effect of gabapentin, this study used two differentially integrated nociceptive tests. We systematically compared the effects of various doses of gabapentin on the paw withdrawal to pressure (PWTP), a spinally coordinated reflex and the vocalization threshold to paw pressure (VTPP), a supra-spinal integrated test in the sciatic nerve constriction rat model of neuropathic pain. In addition, we evaluated the effect of gabapentin on the struggle latency to paw immersion into a non-noxious cold (10 degrees C) water bath. Similar lower doses (1-30 mg/kg) of gabapentin produced potent antinociception in the VTPP test but were devoid of effects on the PWTP. The effect was observed not only on the nerve-injured side, but also, although less pronounced, on the contralateral side. Only the highest dose (100 mg/kg) of the anticonvulsant was able to induce an increase in the nerve-injured paw threshold in both tests. In the thermal test, gabapentin (3, 10 and 30 mg/kg i.p.) dose-dependently increased the response time to the 10 degrees C stimulus. Gabapentin at 100 mg/kg but not at 30 mg/kg produced motor deficits in animals using the rotarod test. Taken together, our findings suggest that low doses of gabapentin have a preferential action on the more integrated pain-related behaviour in neuropathic rats. The present results confirm that gabapentin may be a useful approach for the clinical management of several aspects of neuropathic pain.     

Effects of four herbal extracts on adjuvant-induced inflammation and hyperalgesia in rats.

OBJECTIVE: To evaluate the effects of four herbal medicine extracts on a rat model of inflammatory hyperalgesia. DESIGN/INTERVENTIONS: Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of each rat. Four herbs that are routinely prescribed in Traditional Chinese Medicine for treatment of pain were used: Duhuo (Radix Angelicae Pubescentis), Bai jiang cao (Patriniae Herba cum Radice), Yan hu suo (Rhizoma Corydalis) and Sanqui (Panax Notoginseng). The crude water extracts of the herbs were inected intraperitoneally following a repeated treatment profile. OUTCOME MEASURES: Thermal hyperalgesia was assessed by testing each rat's paw withdrawal response to a noxious thermal stimulus. The magnitude of edema was determined by measuring the maximal thickness of the paw with a caliper. The effect of herb extracts on motor performance was assessed by using an accelerating rotarod test. RESULT: Duhuo, Bai jiang cao, and Yan hu suo significantly attenuated CFA-induced hyperalgesia at 2 hours and facilitated the recovery from hyperalgesia (p < 0.05), when compared to saline-treated rats. The CFA-induced edema was reduced by Duhuo at 24 hours, 72 hours and 168 hours; Bai jiang cao at 24 hours, and Yan hu suo at 24 hours and 168 hours. Sanqi did not produce any significant effect on inflammation and hyperalgesia. The rotarod performance was slightly reduced by Bai jiang cao, Yan hu suo, and Sanqi (p < 0.05) but not by Duhuo treatment. CONCLUSION: The present study identified Duhuo as a selective and effective herbal agent in attenuating persistent hindpaw inflammation and hyperalgesia in rats. These results indicate that some herbal agents may provide an alternative approach to the treatment of persistant inflammatory pain and hyperalgesia.     

Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain

Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.     

Pain threshold in diabetic rats: effects of good versus poor diabetic control.

Pain threshold was assessed via tail flick latency in streptozotocin diabetic rats following a 1-month period of either good or poor diabetic control. Additionally, tail flick latencies were determined under test conditions of euglycemia (60-120 mg/dl) and hyperglycemia (greater than 250 mg/dl) for both groups of diabetic rats. Conditions of hyperglycemia resulted in a significant decrease in tail flick latency in diabetic animals maintained in good as well as poor diabetic control. However, tail flick latencies for animals in the good but not in the poor diabetic control group increased when animals were euglycemic at the time of testing. Animals in the poor diabetic control group continued to have reduced tail flick latencies even after acute normalization of blood glucose levels. These results suggest that chronic states of hyperglycemia that attend prolonged periods of poor diabetic management may lead to persistent alterations in pain threshold. In contrast, the reduced pain threshold of rats maintained in good diabetic control was reversed by a normalization of blood glucose levels. These findings provide evidence for two patterns of hyperalgesia in diabetic rats: (1) a readily reversible form in well-maintained diabetic rats that is altered by reducing circulating blood glucose levels to control values and (2) a more persistent form found in poorly controlled diabetic rats that does not respond to acute normalization of blood glucose.     

Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist.

Metanicotine [N-methyl-4-(3-pyridinyl)-3-butene-1-amine], a novel neuronal nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]nicotine binding sites and it generalized to nicotine in a dose-dependent manner in the drug discrimination procedure. Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-phenylquinone), persistent (Formalin), and chronic (arthritis) pain stimuli. Metanicotine was about 5-fold less potent than nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of nicotine. Nicotinic antagonists, mecamylamine and dihydro-beta-erythroidine, blocked metanicotine-induced antinociception in the different pain models. However, the antinociceptive effect was not affected by pretreatment with either naloxone or by atropine, confirming that metanicotine exerts its antinociceptive effect via nicotinic rather than either opioid or muscarinic mechanisms. In contrast to nicotine, antinociceptive effects of metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that metanicotine is a centrally acting neuronal nicotinic agonist with preferential antinociceptive effects in animals. Thus, metanicotine and related nicotinic agonists may have great potential for development as a new class of analgesics.     

Spinal and supraspinal components of opioid antinociception in streptozotocin induced diabetic neuropathy in rats

This study investigated the antinociceptive effect of opioids given via intraperitoneal and intrathecal routes in a diabetes-induced neuropathic pain model in rats. Streptozotocin induced diabetes in 91% of juvenile male Wistar rats at the dose of 150 mg/kg (75 mg/kg intraperitoneal on 2 successive days). When compared with younger weight-matched saline treated rats, the diabetic rats developed hyperalgesia assessed by the paw pressure nociceptive test. Nociceptive thresholds and responses to fentanyl in all nociceptive tests in these younger normal rats were the same as those described previously for older normal rats. Fentanyl (10-100 microg/kg, i.p.) produced a dose-related antinociceptive effect in both neuropathic (n=6-8) and non-neuropathic (n=6-8) rats in electrical current, paw pressure and tail flick nociceptive tests. Higher doses of fentanyl were needed in neuropathic animals to achieve similar antinociceptive effects to those in non-neuropathic animals. Intrathecal injections of fentanyl (0.05-0.5 microg) in non-neuropathic rats, produced a spinally-mediated, dose-related antinociceptive effect assessed by all tests. In contrast, intrathecal administration of fentanyl that confined the drug action to the spinal cord produced little antinociceptive effect in neuropathic rats in all three tests. These experiments suggest that supraspinal mu opioid receptors are responsible for the antinociceptive effect of opioids in this model of neuropathic pain and that spinal cord opioid systems are in some way rendered ineffective for antinociception assessed with noxious heat, electrical and pressure stimuli.     

Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain

Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the mu-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6mg/kg) and methadone (3mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5h post-injection (P<0.05); codeine (30mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6mg/kg) and methadone (0.5-3mg/kg) robustly attenuated mechanical and cold allodynia for at least 2h post-injection (P<0.05). Codeine (10 and 30mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of mu-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.     

Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H3 receptors.

Histamine H 3 receptors have been suggested to inhibit the activity of a variety of central and peripheral neurons. Recent studies revealed that activation of spinal histamine H 3 receptors attenuates tail pinch, but not tail flick, nociception. To determine whether H 3 receptor-mediated antinociception is truly modality-specific, the effects of the selective H 3 agonist immepip were evaluated on nociceptive responses in rats induced by a range of thermal and mechanical intensities applied to the hind paw and the tail. In addition, the modulation of chemical nociceptive (ie, formalin) responses by immepip was evaluated. Immepip (5 to 30 mg/kg, subcutaneous) attenuated responses to low-intensity mechanical pinch, but not to high-intensity mechanical pressure applied to either the hind paw or the tail. The same doses of immepip had no effect on thermal nociceptive responses, regardless of the stimulus intensity. These results suggest that immepip-induced antinociception is modality- and intensity-specific. It is likely that immepip inhibits low-intensity mechanical nociception by activation of H 3 receptors located on the spinal terminals of Adelta and possibly C high-threshold mechanoreceptors. In addition, immepip (5 mg/kg, subcutaneous) significantly attenuated formalin-induced flinching, but not formalin-induced licking, during both phase 1 and phase 2, suggesting that H 3 agonists might be effective in treating some forms of clinically relevant pain. Certain classes of pain-transmitting fibers possess histamine H 3 receptors, but the localization and functional significance of these inhibitory receptors was not known. The present study shows that drugs that stimulate H 3 receptors can reduce behavioral responses produced by some, but not all, painful stimuli. Thus, H 3 agonists could be a new type of therapy for certain kinds of pain disorders.     

Epidural opioid analgesia in infant rats II: responses to carrageenan and capsaicin.

The aim of this study was to investigate the analgesic effects of epidural opioids upon persistent pain sensitivity in neonatal rat pups. Two models of persistent pain were used, subcutaneous injection of carrageenan, and topical application of capsaicin cream, both to the hind paw. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia were tested at different developmental stages using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21. Rat pups at all three ages displayed a reduction in mechanical (von Frey hair) threshold following carrageenan-induced inflammation of the hind paw that was evident at 3 h and was still present 5 h after application. This effect was greatest in magnitude at P21. This response was blocked by low doses of all three agonists at all ages, relative effectiveness varying with age. Comparison with potencies in acute tests (Marsh, D., Dickenson, A., Hatch, D. and Fitzgerald, M., Epidural opioid analgesia in infant rats I: mechanical and heat responses, Pain 82 (1999) 23-32) show that opioid potency is significantly greater in the presence of carrageenan inflammation at all ages. Topical capsaicin application to the hind paw produced a significant fall in withdrawal latencies to noxious heat. Generally, epidural opioid agonists did not block this C-fibre induced sensitization except at P3, when morphine and DPDPE did prevent the fall in threshold in a dose dependent manner. The results show that newborn rat pups are capable of displaying both allodynia and hyperalgesia following experimental inflammation that is blocked by epidural mu, delta and kappa opioids. The opioid potency is enhanced compared with antinociception in acute tests. This is not observed following capsaicin hyperalgesia and is therefore not a general consequence of C fibre induced increases in central excitability but relies upon mechanisms special to inflammatory pain.     

Amitriptyline prolongs the antihyperalgesic effect of 2‐ or 100‐Hz electro‐acupuncture in a rat model of post‐incision pain

The mechanisms through which electro‐acupuncture (EA) and tricyclic antidepressants produce analgesia seem to be complementary: EA inhibits the transmission of noxious messages by activating supraspinal serotonergic and noradrenergic neurons that project to the spinal cord, whereas tricyclic antidepressants affect pain transmission by inhibiting the reuptake of norepinephrine and serotonin at the spinal level. This study utilized the tail‐flick test and a model of post‐incision pain to compare the antihyperalgesic effects of EA at frequencies of 2 or 100 Hz in rats treated with intraperitoneal or intrathecal amitriptyline (a tricyclic antidepressant). A gradual increase in the tail‐flick latency (TFL) occurred during a 20‐min period of EA. A strong and long‐lasting reduction in post‐incision hyperalgesia was observed after stimulation; the effect after 2 Hz lasting longer than after 100‐Hz EA. Intraperitoneal or intrathecal amitriptyline potentiated the increase in TFL in the early moments of 2‐ or 100‐Hz EA, and the intensity of the antihyperalgesic effect of 100‐Hz EA in both the incised and non‐incised paw. In contrast, it did not significantly change the intensity of the antihyperalgesic effect of 2‐Hz EA. The EA‐induced antihyperalgesic effects lasted longer after intraperitoneal or intrathecal amitriptyline than after saline, with this effect of amitriptyline being more evident after 100‐ than after 2‐Hz EA. The synergetic effect of amitriptyline and EA against post‐incision pain shown here may therefore represent an alternative for prolonging the efficacy of EA in the management of post‐surgical clinical pain.     

Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for α4β2 or for α7 nAChRs were then tested in the formalin and complete Freund’s adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective α4β2 agonist ispronicline and a novel α4β2-selective potentiator did not appear to produce analgesia in either model. α7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective α7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by α4β2 and only minimally by α7 subtypes. Taken with previous studies, the results suggest that agonism of α4β2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.     

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

Numerous studies have demonstrated a physiological interaction between the mu opioid receptor (MOR) and delta opioid receptor (DOR) systems. A few studies have shown that dual MOR-DOR agonists could be beneficial, with reduced tolerance and addiction liability, but are nearly untested in chronic pain models, particularly neuropathic pain. In this study, we tested the MOR-DOR agonist SRI-22141 in mice in the clinically relevant models of HIV Neuropathy and Chemotherapy-Induced Peripheral Neuropathy (CIPN). SRI-22141 was more potent than morphine in the tail flick pain test and had equal or enhanced efficacy versus morphine in both neuropathic pain models, with significantly reduced tolerance. SRI-22141 also produced no jumping behavior during naloxone-precipitated withdrawal in CIPN or naïve mice, suggesting that SRI-22141 produces little to no dependence. SRI-22141 also reduced tumor necrosis factor-α and cyclooxygenase-2 in CIPN in the spinal cord, suggesting an anti-inflammatory mechanism of action. The DOR-selective antagonist naltrindole strongly reduced CIPN efficacy and anti-inflammatory activity in the spinal cord, without affecting tail flick antinociception, suggesting the importance of DOR activity in these models. Overall, these results provide compelling evidence that MOR-DOR agonists could have strong efficacy with reduced side effects and an anti-inflammatory mechanism in the treatment of neuropathic pain.PerspectiveThis study demonstrates that a MOR-DOR dual agonist given chronically in chronic neuropathic pain models has enhanced efficacy with strongly reduced tolerance and dependence, with a further anti-inflammatory effect in the spinal cord. This suggests that MOR-DOR dual agonists could be effective treatments for neuropathic pain with reduced side effects.