Nociceptin (Orphanin FQ) abolishes gestational and ovarian sex steroid-induced antinociception and induces hyperalgesia

Nociceptin (Orphanin FQ) is a newly discovered endogenous heptadecapeptide substrate for the opioid-receptor-like 1 receptor, a G protein coupled receptor that bears striking amino acid sequence homology to opiate receptors. In rats, intrathecal (i.t.) administration of nociceptin is without effect on basal thresholds for responsiveness to electric foot shock. However, during either late gestation or its hormonal simulation, when nociceptive thresholds are elevated by approximately 70%, i.t. nociceptin substantially attenuates jump thresholds in a dose-dependent fashion. This hypoalgesic effect of nociceptin is not limited to attenuating the gestational or sex steroid-induced increment in pain thresholds. Following the highest i.t. dose of nociceptin employed (20 nmol), the gestational or sex steroid-induced increment in jump thresholds is not only abolished but a significant hyperalgesia is observed. These results underscore the importance of the hormonal milieu to nociceptin hypoalgesic sensitivity. The potential contribution of spinal nociceptive pathways that utilize nociceptin to the etiology of extraordinary painful pregnancy and labor should not be ignored.     

Lamotrigine in the treatment of painful diabetic neuropathy

An open trial was conducted to study the potential efficacy of lamotrigine, a novel antiepileptic agent that blocks voltage-sensitive sodium channels and inhibits the release of glutamate, in relieving the pain associated with diabetic neuropathy. Subsequent to a 1 week washout period from previous analgesics, lamotrigine was administered at a dose of 25 mg/day for 1 week. The dose was doubled on a weekly basis up to 400 mg/day over 6 weeks. The McGill pain questionnaire (MPQ), spontaneous pain and a series of mechanical and thermal stimuli-induced pain were measured with the use of 0–100 visual analogue scale (VAS), on seven office visits. Pain level was also recorded by each patient twice daily, 1 week before, during, and 2 weeks after the treatment period with the use of a 0–10 numerical pain scale (NPS). Quantitative mechanical (Von Frey filaments) and thermal testing (QTT), and routine blood tests were performed at the beginning and at the end of the study. Thirteen patients completed the study. Spontaneous pain measured by VAS and NPS gradually dropped from a baseline of 49 ± 8 and 6.8 ± 0.6, to 20 ± 8.6 ( p < 0.001) and 4.3 ± 0.9 ( p < 0.001), respectively, at the end of the treatment period. Similarly, cold allodynia dropped from 38 ± 9.2 to 16 ± 15.3 ( p = 0.01), and the MPQ score from 13.6 ± 0.8 to 11.0 ± 1.5 ( p < 0.01). In contrast, no significant changes were found in the QTT, mechanical pain thresholds and laboratory results. Two patients were withdrawn from the study because of adverse effects. A long-term follow up showed that most patients were still using lamotrigine 6 months after the end of the study. The results of the study suggest that lamotrigine is potentially effective and safe in treating painful diabetic neuropathy.     

己酮可可碱对选择性坐骨神经分支损伤大鼠脊髓星形胶质细胞的影响

目的观察己酮可可碱腹腔注射对选择性坐骨神经分支损伤大鼠(SNI)脊髓星形胶质细胞的影响。方法切断腓总神经和胫神经保留腓肠神经,制作坐骨神经分支选择性损伤模型。雄性SD大鼠48只随机分为:假手术组(Sh)、模型组(SNI)、己酮可可碱组(PTX)。PTX组从术前1d起至术后6d连续7d,每日一次腹腔注射己酮可可碱100mg/kg。观察指标包括:术前1d,术后1、3、5、7、14d的机械缩足反射阈值(MWT)和热缩足反射持续时间(TWD);不同组别脊髓星形胶质细胞标志物GFAP在术后1d、3d、7d、14d的表达。结果大鼠坐骨神经选择性切断后1d起MWT降低,TWD延长,与假手术组比差异显著(p<0.05);己酮可可碱腹腔注射抑制MWT降低和TWD延长,与模型组相比差异显著(p<0.05);己酮可可碱腹腔注射可减少部分坐骨神经切断后脊髓GFAP的表达,减少星形胶质细胞阳性细胞数。结论己酮可可碱腹腔注射可抑制SNI脊髓星形胶质细胞的增生,减轻痛觉超敏和痛觉过敏。     

Mechanisms of Pefloxacin-Induced Pain

In electrophysiological and behavioral experiments on rats we studied the effects of pefloxacin, a member of fluoroquinolone family, on the nociceptive system. Intraperitoneal injection of pefloxacin (80 mg/kg) decreased the thresholds of nociceptive response to noxious stimulation in the hot-plate test. In addition, it decreased the threshold of the late component of nociceptive flexor reflex. Intrathecal application of pefloxacin in a dose of 20 microg provoked allodynia, while the higher dose of 400 microg induced behavioral pattern characteristic of central pain syndrome. It was hypothesized that pain induced by pefloxacin results from disturbances in GABAergic inhibition in the central subdivisions of the nociceptive system.     

Behavioral characteristics of a mouse model of cancer pain

Pain is a major symptom in cancer patients, and most cancer patients with advanced or terminal cancers suffer from chronic pain related to treatment failure and/or tumor progression. In the present study, we examined the development of cancer pain in mice. Murine hepatocarcinoma cells, HCa-1, were inoculated unilaterally into the thigh or the dorsum of the foot of male C3H/HeJ mice. Four weeks after inoculation, behavioral signs were observed for mechanical allodynia, cold allodynia, and hyperalgesia using a von Frey filament, acetone, and radiant heat, respectively. Bone invasion by the tumor commenced from 7 days after inoculation of tumor cells and was evident from 14 days after inoculation. Cold allodynia but neither mechanical allodynia nor hyperalgesia was observed in mice that received an inoculation into the thigh. On the contrary, mechanical allodynia and cold allodynia, but not hyperalgesia, were developed in mice with an inoculation into the foot. Sometimes, mirror-image pain was developed in these animals. These results suggest that carcinoma cells injected into the foot of mice may develop severe chronic pain related to cancer. This animal model of pain would be useful to elucidate the mechanisms of cancer pain in humans.     

Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the α₂δ subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(−)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models.
2. In the rat formalin test, S-(+)-3-isobutylgaba (1–100 mg kg⁻¹) and gabapentin (10–300 mg kg⁻¹) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg⁻¹, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1–10.0 mg kg⁻¹, s.c.). In contrast, the R-(−)-enantiomer of 3-isobutylgaba (1–100 mg kg⁻¹) produced a modest inhibition of the late phase at the highest dose of 100 mg kg⁻¹. However, none of the compounds showed any effect during the early phase of the response.
3. The s.c. administration of either S-(+)-3-isobutylgaba (1–30 mg kg⁻¹) or gabapentin (10–100 mg kg⁻¹), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg⁻¹, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg⁻¹, respectively. In contrast, R-(−)-3-isobutylgaba failed to show any effect in the two hyperalgesia models.
4. The intrathecal administration of gabapentin dose-dependently (1–100 μg/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response.
5. Unlike morphine, the repeated administration of gabapentin (100 mg kg⁻¹ at start and culminating to 400 mg kg⁻¹) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10–300 mg kg⁻¹), R-(−) (3–100 mg kg⁻¹) or S-(+)-3-isobutylgaba (3–100 mg kg⁻¹) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1–100 mg kg⁻¹, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30–300 mg kg⁻¹) and S-(+)-isobutylgaba (1–100 mg kg⁻¹) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus.
6. Gabapentin (30–300 mg kg⁻¹, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

     

Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D2

1. We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the effect of prostaglandins on nociceptin-induced allodynia and hyperalgesia.
2. Prostaglandin D₂ (PGD₂) blocked the allodynia induced by nociceptin in a dose-dependent manner with an IC₅₀ of 26 ng kg⁻¹, but did not affect the nociceptin-induced hyperalgesia at doses up to 500 ng kg⁻¹. BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC₅₀ of 83 ng kg⁻¹.
3. The blockade of nociceptin-induced allodynia by PGD₂ was reversed by the potent and selective DP-receptor antagonist BW A868C in a dose-dependent manner with an ED₅₀ of 42.8 ng kg⁻¹.
4. Glycine (500 ng kg⁻¹) almost completely blocked the nociceptin-induced allodynia. A synergistic effect on the inhibition of nociceptin-evoked allodynia was observed between glycine and PGD₂ at below effective doses.
5. Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin-induced allodynia with an IC₅₀ of 2.9 μg kg⁻¹.
6. PGE₂, PGF_2α, butaprost (an EP₂ agonist) and cicaprost (a PGI receptor agonist) did not affect the nociceptin-induced allodynia.
7. These results demonstrate that PGD₂ inhibits the nociceptin-evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

     

Evidence for opiate-activated NMDA processes masking opiate analgesia in rats

The acute interaction between opioid receptors and N-methyl-D-aspartate (NMDA) receptors on nociception was examined in rats using tail-flick and paw-pressure vocalisation tests. When injected at various times (1 to 6 h) after morphine (5 to 20 mg/kg, i.v.) or fentanyl (4x40 microgram/kg, i.v.), the opioid receptor antagonist naloxone (1 mg/kg, s.c.) not only abolished the opiate-induced increase in nociceptive threshold, but also reduced it below the basal value (hyperalgesia). The noncompetitive NMDA receptor antagonist MK-801 (0.15 or 0.30 mg/kg, s.c.) prevented the naloxone-precipitated hyperalgesia and enhanced the antinociceptive effects of morphine (7.5 mg/kg, i.v.) and fentanyl (4x40 microgram/kg, i.v.). These results indicate that the antinociceptive effects of morphine and fentanyl, two opiate analgesics widely used in humans in the management of pain, are blunted by concomitant NMDA-dependent opposing effects which are only revealed when the predominant antinociceptive effect is sharply blocked by naloxone. This study provides new rationale for beneficial adjunction of NMDA receptor antagonists with opiates for relieving pain by preventing pain facilitatory processes triggered by opiate treatment per se.     

Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitro skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (Adelta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase Aimmunoglobulin G) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their discharge to a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%. By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.