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Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that is effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined the effect of oxcarbazepine and other AEDs in a model of neuropathic pain in the rat and guinea-pig. Oxcarbazepine and carbamazepine (3-100 mg x kg(-1)) did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation in the rat following oral administration. However, in the same model in the guinea-pig, both drugs produced up to 90% reversal of mechanical hyperalgesia with respective D(50) values of 10.7 and 0.8 mg x kg(-1). The active human metabolite of oxcarbazepine, monohydroxy derivative, was similarly active against mechanical hyperalgesia in the guinea-pig but not the rat. Lamotrigine (3-100 mg x kg(-1), p.o.) was effective against mechanical hyperlagesia in both species although it showed greater efficacy and potency in the guinea-pig (D(50) 4.7 mg x kg(-1)) compared to the rat (D(50) 27 mg kg(-1)). Lamotrigine produced slight inhibition of tactile allodynia in the rat only at the highest dose tested of 100 mg x kg(-1). Gabapentin was poorly active against mechanical hyperalgesia in both the rat and guinea-pig following a single oral administration (100 mg x kg(-1)), although upon repeated administration it produced up to 70 and 90% reversal in rat and guinea-pig, respectively. Gabapentin did however produce significant dose-related reversal of tactile allodynia in the rat following a single administration. These data show that oxcarbazepine and other AEDs are effective anti-hyperalgesic or anti-allodynic agents in an animal model of neuropathic pain, and provide further support for their use in the treatment of neuropathic pain in the clinic.

We have 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 behavioural 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 of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h 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 the 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. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.

The excitatory neurotransmitter, glutamate, is particularly important in the transmission of pain information in the nervous system through the activation of ionotropic and metabotropic glutamate receptors. A potent, subtype-selective antagonist of the metabotropic glutamate-5 (mGlu5) receptor, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has now been discovered that has effective anti-hyperalgesic effects in models of inflammatory pain. MPEP did not affect rotarod locomotor performance, or normal responses to noxious mechanical or thermal stimulation in naive rats. However, in models of inflammatory pain, systemic administration of MPEP produced effective reversal of mechanical hyperalgesia without affecting inflammatory oedema. In contrast to the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac, the maximal anti-hyperalgesic effects of orally administered MPEP were observed without acute erosion of the gastric mucosa. In contrast to its effects in models of inflammatory pain, MPEP did not produce significant reversal of mechanical hyperalgesia in a rat model of neuropathic pain.

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.

Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.

We have examined the effects of a novel GABA(B) agonist, CGP35024, in models of chronic neuropathic (partial sciatic ligation) and inflammatory (Freund's complete adjuvant) pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-baclofen and gabapentin. CGP35024 and L-baclofen reversed neuropathic mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect inflammatory mechanical hyperalgesia. Gabapentin only moderately affected neuropathic hyperalgesia following a single administration by either route, but produced significant reversal following daily administration for 5 days. It was only weakly active against inflammatory hyperalgesia following single or repeated administration. The antihyperalgesic effects of L-baclofen and CGP35024, but not gabapentin, were blocked by the selective GABA(B) receptor antagonist CGP56433A. CGP35024 was seven times more potent against neuropathic hyperalgesia than in the rotarod test for motor co-ordination, whilst L-baclofen was approximately equipotent in the two tests. In the isolated hemisected spinal cord from the rat, CGP35024, L-baclofen and gabapentin all inhibited capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-baclofen, but not gabapentin, also inhibited the polysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as the 'wind-up' response to repetitive stimulation. These data indicate that CGP35024 and L-baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia, and that CGP35024 has a therapeutic window for antihyperalgesia over spasmolysis.

The excitatory neurotransmitter, glutamate, is particularly important in the transmission of pain information in the nervous system through the activation of ionotropic and metabotropic glutamate receptors. A potent, subtype-selective antagonist of the metabotropic glutamate-5 (mGlu5) receptor, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has now been discovered that has effective anti-hyperalgesic effects in models of inflammatory pain. MPEP did not affect rotarod locomotor performance, or normal responses to noxious mechanical or thermal stimulation in naïve rats. However, in models of inflammatory pain, systemic administration of MPEP produced effective reversal of mechanical hyperalgesia without affecting inflammatory oedema. In contrast to the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac, the maximal anti-hyperalgesic effects of orally administered MPEP were observed without acute erosion of the gastric mucosa. In contrast to its effects in models of inflammatory pain, MPEP did not produce significant reversal of mechanical hyperalgesia in a rat model of neuropathic pain.

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.

The cardiotoxicity of allylamine (AA) is considered to be mediated by metabolism to the highly reactive aldehyde, acrolein (ACR). The toxicity of AA to myocardial myocyte reaggregate cultures (MMR) was assessed by measuring percentage beating as a marker of functional viability. The studies demonstrated that AA toxicity could be prevented by inhibitors of benzylamine oxidase (BZO) but not by inhibitors of monoamine oxidase A or B. Addition of exogenous BZO markedly potentiated the toxicity, an effect that could be blocked by semicarbazide, an inhibitor of BZO. The present studies support the view that AA is metabolized by BZO to the proximate toxicant, ACR. In serum-free cultures, high concentrations (0.5–2.5 m m ) of AA were required to cause any loss of viability, and as the concentration of serum in the medium was increased so the loss of viability was induced by AA; in MMR maintained in 50% foetal calf serum, all viability was lost after 3 hr of exposure to 100 μ m -AA. Mercaptoethanesulphonate (MESNA), a scavenger of reactive species that is known not to penetrate myocytes, prevented the toxicity both of 100 μ m -AA and 100 μ m -ACR to MMR in serum-supplemented medium. In contrast, when MMR in serum-free medium were exposed to high concentrations of AA, MESNA had no moderating effect. These findings suggest that AA undergoes extracellular metabolism to ACR in serum-supplemented medium because of the presence of BZO in serum. It is clear that extracellular metabolism is of great importance in the pathogenesis of AA-induced toxicity to MMR in serum-supplemented medium. The toxicity of AA was also prevented by the iron chelator desferrioxamine (DF) at a concentration shown not to inhibit significantly the activity of BZO. ACR toxicity too, was inhibited by DF. This suggests a role for free radicals in the toxicity of AA to MMR, as DF chelates iron, thus preventing the catalysis of free radical reactions (Halliwell and Gutteridge, 1986). Addition of α-tocopherol succinate, an inhibitor or lipid peroxidation, to the cultures also reduced the toxicity of AA, which provides some evidence of the role of lipid peroxidation in the mechanism of AA toxicity to MMR. That process too, commonly involves free radical mechanisms. The results are discussed with reference to the action of AA in vivo, in order to consider whether extracellular metabolism might be of importance in the mechanism of toxicity to the whole animal.

This study investigated the response of chick myocardial myocyte reaggregates (MMR) to allylamine, which is specifically toxic to the cardiovascular system, and its putative toxic metabolite, acrolein. Toxicity was assessed by determining cellular ATP content, spontaneous beating and ultrastructural alterations. Both allylamine and acrolein caused a dose-dependent loss of beating and depletion of cellular ATP content. Treatment with either 10 or 100 mum-allylamine produced marked alterations in reaggregate tissue morphology at all times, which was characterized by widespread myocyte necrosis and a reduction in tissue compactness. Exposure of aggregates to acrolein produced generalized tissue destruction following administration of either 10 or 100 mum-acrolein. The concentration of allylamine required to cause loss of MMR beating was greatly increased when incubations were carried out in serum-free medium. It is suggested that the presence of benzylamine oxidase in serum contributes to the toxicity of allylamine to MMR, by metabolizing allylamine to acrolein. This proposal is supported by the finding that the related amines n-methylallylamine and diallylamine had no effect on spontaneous beating, which may be because they are very poor substrates for benzylamine oxidase. The data presented demonstrate that allylamine is highly toxic to MMR, and we believe that further investigations into the role of serum in allylamine toxicity would improve our understanding of the biochemical basis of its action.

1. The involvement of the haloperidol-sensitive, sigma recognition site and the N-methyl-D-aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047), has been investigated in the rat by use of a two-lever, operant drug discrimination paradigm. 2. Six compounds with nanamolar affinity for the sigma recognition site [+/-)-pentazocine, (+)-3-(hydroxyphenyl)-N-propylpiperidine [+)-3-PPP), ditolylguanidine (DTG), haloperidol, (-)-butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)-NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]-DTG from the central sigma recognition site by more than 40%. 3. While (+/-)-pentazocine (in the presence of naloxone) generalised and (+)-3-PPP partially antagonised the (+)-NANM cue, the other putative sigma ligands were ineffective either as agonists or antagonists at doses clearly occupying the sigma site in vivo. 4. Dose-dependent generalisation to the (+)-NANM cue was seen with the selective non-competitive NMDA receptor antagonist, MK-801, a compound devoid of significant affinity for the sigma recognition site. 5. (+/-)-Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)-NANM discriminative stimulus and their potencies as anticonvulsants. 6. In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)-NANM are mediated by the haloperidol-sensitive sigma recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.