鞘内注射催产素对大鼠神经痛反应的影响

目的 :观察不同剂量催产素对神经痛大鼠热痛敏的影响。方法 :在脊神经结扎致坐骨神经损伤大鼠模型上采用辐射热缩腿反射的方法 ,以抬脚潜伏期作为观察指标。结果 :蛛网膜下腔注射催产素 (1ng ,2 5ng ,5ng)对神经痛大鼠有镇痛作用 ,呈剂量相关关系。结论 :鞘内注射催产素对神经痛大鼠有镇痛作用。     

Involvement of a spinal brain-derived neurotrophic factor/full-length TrkB pathway in the development of nerve injury-induced thermal hyperalgesia in mice

Partial sciatic nerve ligation in mice caused a marked and persistent decrease in the latency of paw withdrawal from a thermal stimulus only on the ipsilateral side. This thermal hyperalgesia was abolished by repeated intrathecal pretreatment with a specific antibody to brain-derived neurotrophic factor (BDNF), but not neurotrophin-4, just before and after the nerve ligation. These results provide direct evidence that BDNF within the spinal cord may contribute to the development of thermal hyperalgesia caused by nerve injury in mice. We previously reported that protein level of full-length TrkB, which contains the cytoplasmic protein tyrosine kinase domain, were clearly increased on the ipsilateral side of spinal cord membranes obtained from sciatic nerve-ligated mice. In the present study, we further demonstrated that the increased in the protein level of full-length TrkB is completely reversed by concomitant intrathecal injection of BDNF antibody. Furthermore, thermal hyperalgesia induced by nerve ligation was completely suppressed by repeated intrathecal injection of a specific antibody to full-length TrkB and an inhibitor of the protein tyrosine kinase activity for the neurotrophin receptor, K-252a. However, repeated intrathecal injection of a specific antibody to truncated TrkB, which lacks the cytoplasmic protein tyrosine kinase domain, failed to reverse thermal hyperalgesia observed in nerve-ligated mice. These findings suggest the possibility that the binding of BDNF to full-length TrkB and subsequent its activation may play a critical role in the development of neuropathic pain-like thermal hyperalgesia induced by nerve injury in mice.     

Differential effects of intrathecally administered N- and P-type voltage-sensitive calcium channel blockers upon two models of experimental mononeuropathy in the rat

We investigated the effects of intrathecally administered N-type and P-type voltage-sensitive calcium channel (VSCC) blockers on the level of thermal hyperalgesia in two neuropathic pain models: the chronic constriction injury (CCI) model and the partial sciatic nerve injury (PSNI) model. N-type, but not P-type, VSCC blockers attenuated the level of thermal hyperalgesia induced by CCI in a dose-dependent manner. In the PSNI model, both N-type and P-type VSCC blockers had no effect on thermal hyperalgesia. This suggests that some types of neuropathic pain may be treatable with N-type VSCC blockers.     

Involvement of spinal neurokinin-1 receptors in the maintenance but not induction of carrageenan-induced thermal hyperalgesia in the rat

The study was undertaken to assess the antihyperalgesic effect of L-732,138, (N-acetyl-L-tryptophan-3,5-bistrifluoromethyl benzyl ester), a non-peptide neurokinin-1 (NK1) receptor antagonist in rats when given intrathecally. The peripheral inflammation associated with behavioral hyperalgesia to a thermal stimulus was induced by intraplantar (i.pl.) injection of carrageenan. The thermal hyperalgesia was measured by paw withdrawal latency. Intrathecal (i.t.) injection of L-732,138 (100 nmol) at 3h after carrageenan markedly attenuated the paw withdrawal latency of the inflamed paw, but not that of the non-inflamed paw. L-732,138 (100 nmol, i.t.) given 10 min prior to carrageenan injection had no effect on the carrageenan-induced decrease in paw withdrawal latency to noxious thermal stimulus. The results demonstrate that NK1 receptor is involved in the maintenance but not the induction and development of thermal hyperalgesia evoked by carrageenan.     

Effects of nociceptin on cardiac norepinephrine and acetylcholine release evoked by ouabain

We investigated whether the novel peptide, nociceptin, modulates neuronal transmission at autonomic nerve endings. Using a cardiac dialysis technique, the effects of locally applied nociceptin on cardiac acetylcholine (ACh) and norepinephrine (NE) release were examined in anesthetized cats. Dialysis probes were implanted in the left ventricular wall, with the concentration of dialysate NE or ACh serving as an indicator of NE or ACh output at cardiac sympathetic or parasympathetic nerve endings. Locally applied ouabain evoked increases in NE and ACh output. Nociceptin suppressed the ouabain induced ACh increment. The ouabain induced NE release was not altered by nociceptin. However, in the presence of desipramine (a NE uptake inhibitor), nociceptin suppressed the ouabain-induced NE release. Inhibition by nociceptin of ouabain-induced release of NE or ACh was blocked by pretreatment with nocistatin (a nociceptin action blocking peptide). Nociceptin-induced inhibition of ACh or NE release is attributable to pre-synaptic modulation rather than a reversal of the ouabain effect. These findings demonstrate that nociceptin inhibits cardiac autonomic neurotransmission via a presynaptic opioid receptor-like1(ORL1) receptor.     

Evidence for a localization of [(3)H]nociceptin binding sites on medullar primary afferent fibers

The ORL1 receptor (opioid receptor-like 1) and its endogenous ligand, nociceptin, are involved in nociperception. We have studied, in a deafferented animal model, the modification of medullar [(3)H]nociceptin binding site density. A rhizotomy was carried out in rats at the cervicothoracic level, and the dorsal afferent fibers from C5 to T1 were lesioned. Seven days after surgery, animals were sacrificed, and the binding of [(3)H]nociceptin (2 nM) was then performed on spinal cord sections. An autoradiographic analysis revealed a significant reduction (-18%) of [(3)H]nociceptin binding site density in the dorsal horn ipsilateral to the deafferentation compared with the contralateral side of the lesion. In the ventral horn, no significant difference (-5%) of binding was observed in the ipsilateral side of the deafferentation compared with the contralateral side. Thus, [(3)H]nociceptin binding sites appear to be located mainly on either interneurons or deutoneurons of the spinal cord, because the bulk of the labeling is spared by the lesion. However, the significant reduction of labeling that occurs on the dorsal part of the ipsilateral side to the lesion indicates that [(3)H]nociceptin binding sites are also present on these dorsal afferent fibers.     

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

ObjectiveIn this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested.MethodsIn 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system.ResultsHFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS.ConclusionsHFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system.SignificanceOur neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans.     

Normal sensitivity to acute pain,but increased inflammatory hyperalgesia in mice lacking the nociceptin precursor polypeptide or the nociceptin receptor

Nociceptin/orphanin FQ (N/OFQ) is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). It is released from a larger precursor polypeptide, called prepro-nociceptin (ppN/OFQ) from which, in addition to N/OFQ, other biologically active neuropeptides may be derived. Increasing evidence indicates that exogenous application of N/OFQ to the central nervous system of mice and rats induces pro- and antinociceptive effects depending on the dose and site of administration. Much less is known about a potential contribution of endogenous N/OFQ to pain control. Here, we have used a genetic approach to address this topic. Mice deficient in either the NOP receptor (NOP-R-/- mice) or the N/OFQ precursor polypeptide (ppN/OFQ-/- mice) or both (double knockout mice) were compared with wild-type littermates in animal models of acute and tonic pain. Nociceptive responses to acute noxious heat of all three types of mutant mice were indistinguishable from those of wild-type mice. Accordingly, nociceptive behaviour was very similar in the early phase of the formalin test. However, NOP-R-/-, ppN/OFQ-/- and double knockout mice showed markedly stronger nociceptive responses during prolonged nociceptive stimulation in the second phase of the formalin test and significantly lower thermal pain thresholds in inflamed tissue after zymosan A injection. These results indicate that N/OFQ contributes significantly to endogenous pain control during prolonged nociceptive stimulation but does not affect acute pain sensitivity. Among the three types of mutant mice nociceptive behaviour was nearly identical, indicating that the lack of other potential ppN/OFQ products in the ppN/OFQ-/- mice was apparently without effect on the nociceptive phenotype.     

Comparison of the spinal neuropathic pain induced by intraspinal injection of N-methyl-d-aspartate and quisquate in rats

Objective

Excitatory amino acids play important roles in the development of secondary pathology following spinal cord injury (SCI). This study was designed to evaluate morphological changes in the dorsal horn of the spinal cord and assess profiles of pain behaviors following intraspinal injection of N-methyl-D-aspartate (NMDA) or quisqualate (QUIS) in rats.

Methods

Forty male Sprague-Dawley rats were randomized into three groups : a sham, and two experimental groups receiving injections of 125 mM NMDA or QUIS into their spinal dorsal horn. Following injection, hypersensitivity to cold and mechanical stimuli, and excessive grooming behaviors were assessed serially for four weeks. At the end of survival periods, morphological changes in the spinal cord were evaluated.

Results

Cold allodynia was developed in both the NMDA and QUIS groups, which was significantly higher in the QUIS group than in the NMDA group. The mechanical threshold for the ipsilateral hind paw in both QUIS and NMDA groups was significantly lower than that in the control group. The number of groomers was significantly higher in the NMDA group than in the QUIS group. The size of the neck region of the spinal dorsal horn, but not the superficial layer, was significantly smaller in the NMDA and QUIS groups than in the control group.

Conclusion

Intraspinal injection of NMDA or QUIS can be used as an excitotoxic model of SCI for further research on spinal neuropathic pain.     

Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: mediation by spinal adrenergic and serotonergic receptors

The present study was performed to examine the effects of electroacupuncture (EA) on cold allodynia and its mechanisms related to the spinal adrenergic and serotonergic systems in a rat model of neuropathic pain. For the neuropathic surgery, the right superior caudal trunk was resected at the level between S1 and S2 spinal nerves innervating the tail. Two weeks after the nerve injury, EA stimulation (2 or 100 Hz) was delivered to Zusanli (ST36) for 30 min. The behavioral signs of cold allodynia were evaluated by the tail immersion test [i.e., immersing the tail in cold water (4 degrees C) and measuring the latency to an abrupt tail movement] before and after the stimulation. And then, we examined the effects of intrathecal injection of prazosin (alpha1-adrenoceptor antagonist, 30 microg), yohimbine (alpha2-adrenoceptor antagonist, 30 microg), NAN-190 (5-HT1A antagonist, 15 microg), ketanserin (5-HT2A antagonist, 30 microg), and MDL-72222 (5-HT3 antagonist, 12 microg) on the action of EA stimulation. Although both 2 Hz and 100 Hz EA significantly relieved the cold allodynia signs, 2 Hz EA induced more robust effects than 100 Hz EA. In addition, intrathecal injection of yohimbine, NAN-190, and MDL-72222, but not prazosin and ketanserin, significantly blocked the relieving effects of 2 Hz EA on cold allodynia. These results suggest that low-frequency (2 Hz) EA is more suitable for the treatment of cold allodynia than high-frequency (100 Hz) EA, and spinal alpha2-adrenergic, 5-HT1A and 5-HT3, but not alpha1-adrenergic and 5-HT2A, receptors play important roles in mediating the relieving effects of 2 Hz EA on cold allodynia in neuropathic rats.     

Intrathecal high dose morphine produces hyperalgesia in the rat

Intrathecal microinjections of high doses of morphine in the rat produce algesia, hyperalgesia and hypersthesia as opposed to the analgesia found at lower doses. This hyperalgesia is not naloxone reversible and is only partially stereospecific. Morphine-3-glucuronide produces the hyperalgesia at low doses. This morphine-hyperalgesia may be mediated by a class of receptors similar to that which produces opiate-induced central excitation.     

Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain

Spinal N-methyl d-aspartate receptor (NMDAR) plays a pivotal role in nerve injury-induced central sensitization. Recent studies suggest that NMDAR also contributes to neuron-astrocyte signaling. c-Jun N-terminal kinase (JNK) is persistently and specifically activated (indicated by phosphorylation) in spinal cord astrocytes after nerve injury and thus it is considered as a dependable indicator of pain-related astrocytic activation. NMDAR-mediated JNK activation in spinal dorsal horn might be an important form of neuron-astrocyte signaling in neuropathic pain. In the present study, we observed that intrathecal injection of MK-801, a noncompetitive NMDA receptor antagonist, or Ro25-6981 and ifenprodil, which are selective antagonists of NR2B-containing NMDAR each significantly reduced nerve injury-induced JNK activation. Double immunostaining showed that NR2B was highly expressed in neurons, indicating the effect of NMDAR antagonists on JNK activation was indirect. We further observed that intrathecal injection of NMDA (twice a day for 3 days) significantly increased spinal JNK phosphorylation. Besides, NMDAR-related JNK activation could be blocked by a neuronal nitric oxide synthase (nNOS) selective inhibitor (7-nitroindazole sodium salt) but not by a nNOS sensitive guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Finally, real-time RT-PCR and immunostaining showed that nerve injury-induced interleukin-1beta expression was dependent on astrocytic JNK activation. Treatments targeting NMDAR-nNOS pathway also influenced interleukin-1beta expression, which further confirmed our hypothesis. Taken together, our results suggest that neuronal NMDAR-nNOS pathway could activate astrocytic JNK pathway. Excitatory neuronal transmission initiates astrocytic activation-induced neuroinflammation in this way, which contributes to nerve injury-induced neuropathic pain.     

Post-injury treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.     

Involvement of tachykinin NK1 receptors in nociceptin-induced hyperalgesia in mice

Intrathecal (i.t.) injection of nociceptin at small doses (3.0 and 30.0 fmol) produced a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of nociceptin (3.0 fmol) and returned to control level within 30 min. Hyperalgesia elicited by nociceptin was inhibited dose-dependently by i.t. co-administration of tachykinin NK₁ receptor antagonists, CP-99,994 and sendide. A significant antagonistic effect of [ -Phe⁷, -His⁹] substance P (6–11), a selective antagonist for substance P, was observed against the nociceptin-induced hyperalgesia. Pretreatment with i.t. substance P antiserum and i.t. capsaicin resulted in a complete block of the reduced threshold produced by nociceptin. The NK₂ receptor antagonist, MEN-10,376 and pretreatment with neurokinin A antiserum did not alter the behavioural effect of nociceptin. The N-methyl- -aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and (−)-2-amino-5-phosphonovaleric acid ( -APV), and -N^G-nitro arginine methyl ester ( -NAME), a nitric oxide synthase inhibitor, failed to inhibit nociceptin-induced hyperalgesia. The results obtained suggest that the hyperalgesic effect of nociceptin may be mediated through tachykinin NK₁ receptors in the spinal cord.     

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative autoradiographic mapping of the ORL1, μ-, δ- and κ-receptors in the brains of knockout mice lacking the ORL1 receptor gene

Until recently the opioid receptor family was thought to consist of only the μ-, δ- and κ-receptors. The cloning of opioid receptor like receptor (ORL1) and its endogenous ligand nociceptin/orphanin FQ, which displayed anti-opioid properties, has raised the issue of functional co-operativity of this system with the classical opioid system. ORL1 receptor knockout mice have been successfully developed by homologous recombination to allow the issue of potential heterogeneity of this receptor and also of compensatory changes in μ-, δ- or κ-receptors in the absence of ORL1 to be addressed. We have carried out quantitative autoradiographic mapping of these receptors in the brains of mice that are wild-type, heterozygous and homozygous for the deletion of the ORL1 receptor. ORL1, μ-, δ- and κ-receptors were labelled with [³H] leucyl-nociceptin (0.4 nM), [³H] DAMGO (4 nM), [³H] deltorphin-I (7 nM), and [³H] CI-977 (2.5 nM) respectively. An approximately 50% decrease in [³H] leucyl-nociceptin binding was seen in heterozygous ORL1 mutant mice and there was a complete absence of binding in homozygous brains indicating the single gene encodes for the ORL1 receptor and any putative subtypes. No significant gross changes in the binding to other opioid receptors were seen across genotypes in the ORL1 mutant mice demonstrating a lack of major compensation of classical opioid receptors in the absence of ORL1. There were a small number of region specific changes in the expression of classical opioid receptors that may relate to interdependent function with ORL1.     

Nociceptive responses and spinal plastic changes of afferent C-fibers in three neuropathic pain models induced by sciatic nerve injury in the rat

Peripheral nerve injuries induce plastic changes on primary afferent fibers and on the spinal circuitry, which are related to the emergence of neuropathic pain. In this study we compared three models of sciatic nerve injury in the rat with different degrees of damage and impact on regeneration capability: crush nerve injury, chronic constriction injury (CCI) and spared nerve injury (SNI). All three models were characterized by means of nerve histology, in order to describe the degenerative and regenerative process of injured axons. Nociceptive responses were evaluated by mechanical and thermal algesimetry tests. Crush animals displayed higher withdrawal thresholds on the ipsilateral paw compared to the contralateral during the time of denervation, while CCI and SNI animals showed mechanical and thermal hyperalgesia. Central plasticity was evaluated by immunohistochemical labeling of non-peptidergic (IB4-positive) and peptidergic (substance P-positive) nociceptive C-fibers on L4-L6 spinal cord sections. After crush nerve injury and SNI, we observed progressive and sustained reduction of IB4 and SP immunolabeling at the sciatic projection territory in the superficial laminae of the dorsal horn, which affected only the tibial and peroneal nerves projection areas in the case of SNI. After CCI, changes on SP-immunoreactivity were not observed, and IB4-immunoreactive area decreased initially but recovered to normal levels on the second week post-injury. Thus, nociceptive responses depend on the type of injury, and the immunoreactivity pattern of afferent fibers at the spinal cord display changes less pronounced after partial than complete sciatic nerve injury. Although signs of neuropathic pain appear in all three lesion models, nociceptive responses and central plasticity patterns differ between them.     

Effect of intrathecally administered noradrenergic antagonists on nociception in the rat

Recent evidence suggests that some groups of noradrenergic neurons found in the brainstem have axonal connections in the spinal cord dorsal horn and may be involved in the control of pain sensitivity. Such evidence includes the demonstration that intrathecal injection of noradrenergic agonists increases nociceptive threshold (hypoalgesia). The present studies examined whether the descending noradrenergic system is tonically active and, if so, what noradrenergic receptor subtypes mediate the actions of endogenously-released norepinephrine. These studies involved the measurement of nociceptive threshold before and after the intrathecal injection of noradrenergic antagonists having different relative affinities for α-noradrenergic receptor subtypes.The intrathecal administration of α-noradrenergic antagonists produced a dose-dependent decrease in nociceptive threshold (hyperalgesia). This finding is consistent with the proposal that tonically-active bulbospinal noradrenergic neurons modulate the processing of nociceptive information in the spinal cord. The potency and duration of the hyperalgesia was correlated with the relative potency of the antagonists for the α-2 noradrenergic receptor. The relative potencies were as follows: yohimbine > phentolamine > WB 4101 > prazosin. Thus, endogenous norepinephrine which is tonically released from bulbospinal axon terminals may interact preferentially with noradrenergic receptors of the α-2 type.     

Nociceptin/orphanin FQ into the rat periaqueductal gray decreases the withdrawal latency to heat and loading, an effect reversed by (Nphe)nociceptin(1–13)NH2

The present study investigated the effect of intraperiaqueductal grey injection of nociceptin/orphanin FQ (N/OFQ) and an antagonist (Nphe¹)nociceptin(1–13)NH₂ on the hindpaw withdrawal response to thermal and mechanical stimulation in rats. N/OFQ (5 nmol) significantly decreased the nociceptive thresholds in both tests and 1, 5 and 10 nmol of (Nphe¹)nociceptin(1–13)NH₂ significantly reversed this effect in a dose dependent way. Our results demonstrate, that N/OFQ has a nociceptive action, possibly through inhibition of PAG neurons. This effect is blocked by the antagonist (Nphe¹)nociceptin(1–13)NH₂ probably via ORL1 receptors in the periaqueductal grey.