Spinal substance P and N-methyl-D-aspartate receptors are coactivated in the induction of central sensitization of the nociceptive flexor reflex.

We have studied the effects and interactions of the neurokinin-1 receptor antagonist CP-96,345 and the N-methyl-D-aspartate receptor/channel blocker MK-801, both applied intravenously, on the flexor reflex and on the facilitation of the flexor reflex by conditioning stimulation of cutaneous C-afferents in decerebrate, spinalized, unanesthetized rats. The flexor reflex was evoked by subcutaneous electrical stimuli applied to the sural nerve innervation area 1/min at an intensity that activated C-fibers and was recorded as electromyogram from the ipsilateral hamstring muscles. The magnitude of the baseline flexor reflex was usually highly stable in the course of the experiments without experimental manipulations. The same stimulus was used as a conditioning train (0.9 Hz, 20 shocks) and caused a brief facilitation of the flexor reflex, which was maximal 0.5 and 1 min after stimulation (255.1 +/- 23.6% over baseline). During the course of the conditioning stimulus train, the reflex magnitude was gradually increased (wind-up). MK-801 (0.1 and 0.5 mg/kg) consistently depressed the polysynaptic flexor reflex. At a dose of 0.5 mg/kg, but not 0.1 mg/kg, MK-801 reduced the wind-up and blocked the facilitation of the flexor reflex induced by the conditioning stimulus by 90%. The facilitatory effect of 7 pmol intrathecal substance P was also partially reduced by MK-801. CP 96,345 (1 and 3 mg/kg) did not depress the flexor reflex, but dose-dependently antagonized reflex facilitation by the conditioning stimulus train, similarly to its antagonism of intrathecally applied 7 pmol substance P-induced facilitation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glutamate and tachykinin receptors in central sensitization of withdrawal reflexes in the decerebrated rabbit

This study assessed the involvement of NMDA and group I metabotropic glutamate receptors, and tachykinin NK1 and NK3 receptors, in central sensitization of withdrawal reflexes in the decerebrated rabbit. Reflexes evoked in the ankle flexor tibialis anterior and the knee flexor semitendinosus by electrical stimulation at the base of the toes were enhanced for 29-63 min after application of 20% mustard oil to the tips of the toes. Selective antagonists of mGlu1, mGlu5, NMDA and NR2B-subunit-containing NMDA glutamate receptors, as well as NK1, and NK3 receptors, and a non-selective blocker of all tachykinin receptors, were assessed for their effects on the magnitude and duration of the increase in reflexes induced by mustard oil. Dizocilpine, an antagonist of all NMDA receptors (1 mg intrathecal) abolished facilitation of tibialis anterior reflexes and significantly reduced the magnitude and duration of increase of the semitendinosus response. The NR2B-subtype selective antagonist CP-101,606 decreased the magnitude of facilitation of both reflexes but had no effect on duration of enhancement. Selective antagonists for the mGlu1 (CPCCOEt, 1-3 mg intrathecal), mGlu5 (MPEP, 0.2-1 mg intrathecal), NK1 (L-733,060, 0.3 mg intrathecal) or NK3 (SR 142,801, 1 mg kg(-1) i.v.) receptors had no effect on the amplitude or duration of sensitization. However, the non-selective tachykinin receptor blocker ZD-6021 (0.3 mg intrathecal) reduced the amplitude but not the duration of sensitization in the flexor reflexes. Combination of ZD-6021 with CP-101,606 (doses as above) decreased both aspects of the sensitization response. Dizocilpine reduced reflexes evoked from the heel per se, and dizocilpine, CP-101,606 and ZD-6021 reduced arterial blood pressure. Otherwise the drugs used had no effects on baseline variables. The present data confirm the importance of NMDA receptors as a critical part of the process of central sensitization, provide no evidence for a role of metabotropic glutamate receptors, and show that simultaneous blockade of all tachykinin receptors is required to reveal their role in hyperalgesia. The data further indicate that a combined pharmacological approach offers a potential way forward for the development of new antihyperalgesic agents.     

Peculiarities of the development of analgesic effect during transcutaneous dynamic electrical stimulation

The effect of transcutaneous dynamic electrical neurostimulation on the development of analgesia was studied in behavioral and electrophysiological experiments on rats. A 30-min dynamic electrical stimulation elevated the nociception threshold in tail-flick and hot plate tests, increased the threshold of the late nociceptive flexor reflex, and decreased the number of bursts in the response. Intraperitoneal injection of naloxone (2 mg/kg) abolished the analgesic effect of dynamic electrical neurostimulation. It is concluded that the key role in reflex analgesia during dynamic electrical neurostimulation is played by the endogenous cerebral opioid system, which inhibits the nociceptive signals traveling to CNS via unmyelinated C-fiber afferents.     

On the role of NK-2 tachykinin receptors in the mediation of spinal reflex excitability in the rat.

The effects of intrathecal administration of neurokinin A, substance P and [Tyr5, D-Trp6,8,9 Arg10]neurokinin A-(4-10) (Men 10207), a specific NK-2 receptor antagonist, on the spinal nociceptive flexor reflex were studied in decerebrate, spinalized, unanesthetized rats. Intrathecal neurokinin A and substance P facilitate the flexor reflex in a similar manner. The reflex facilitation to intrathecal neurokinin A, but not substance P, is dose-dependently blocked by pretreatment with Men 10207. The NK-2 receptor antagonist by itself facilitates the flexor reflex with a potency about 10 times less than that of neurokinin A, indicating a partial agonistic property. Reversible depression of the flexor reflex, which is not due to nonspecific spinal blockade, is observed after 700 pmol Men 10207. Further increasing the dose of Men 10207 to 7 nmol for 20 s at an intensity that activates unmyelinated (C) fibers stimulation of peripheral nerves at 1 Hz for 20 s at an intensity that activates unmyelinated (C) fibers facilitates the ipsilateral flexor reflex. The duration of the facilitation after conditioning stimulation of the cutaneous sural nerve is several minutes and about 1 h after conditioning stimulation of the gastrocnemius muscle nerves. Pretreatment with Men 10207 (70-700 pmol) has no effect on facilitation by the sural nerve conditioning stimulation, but effectively blocks the long-term reflex facilitation to the gastrocnemius nerve stimulation. The present results indicate a distinct role for NK-2 tachykinin receptors in mediation of spinal reflex excitability in the rat. Neurokinin A may be involved in the long-term increase of spinal reflex excitability after activation of unmyelinated fibers innervating muscle.     

Adenosine receptor antagonists inhibit the development of morphine sensitization in the C57BL/6 mouse.

We examined the effects of adenosine antagonists on the development of morphine sensitization in C57BL/6 mice. Adenosine antagonists or vehicle were repeatedly co-administered intraperitoneally with morphine (10 mg/kg, s.c.) to mice once every other day for 9 days. Two days later, a 10 mg/kg morphine-only challenge was administered to each group. Consistent with sensitization, mice receiving morphine alone developed enhanced ambulatory activity responses to subsequent morphine administrations and, upon morphine-only challenge, had a significantly greater response to morphine than vehicle pretreated animals. The nonselective adenosine antagonist, caffeine, at 10 and 20 mg/kg but not at 5 mg/kg, attenuated the development of sensitization during co-administration with morphine and also following morphine-only challenge. The adenosine A1 selective antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX), at 0.001 and 0.002 mg/kg but not at 0.2 mg/kg, similarly attenuated the development of morphine sensitization. We propose a mechanism which involves an adenosine receptor role in the mesolimbic dopamine system.     

Tramadol induces conditioned place preference in rats: Interactions with morphine and buprenorphine

Surveys and drug surveillance have demonstrated that the abuse liability of tramadol is considerably low in the general population but appears to be higher in opiate addicts, and this difference could attribute to the poly-drug abuse of opioid addicts, although this hypothesis has not been tested in the laboratory. The present study examined the interactions between tramadol and a full μ opioid receptor agonist morphine or a partial μ opioid receptor agonist buprenorphine in a conditioned place preference (CPP) paradigm in rats. Rats were conditioned with tramadol (2–54 mg/kg, i.p.), morphine (0.125–8 mg/kg, s.c.), buprenorphine (0.01–0.316 mg/kg, s.c.) or a combination of a subeffective dose of tramadol (2 mg/kg) with a subeffective dose of morphine or buprenorphine and the CPP effect was measured. The retention of CPP effect was also examined. Tramadol, morphine and buprenorphine all produced a dose-dependent and significant CPP. A smaller dose of tramadol (2 mg/kg) enhanced morphine- and buprenorphine-induced CPP and shifted the dose-effect curves of both drugs leftward. In addition, the combination of tramadol with morphine or buprenorphine prolonged the retention of CPP. These findings indicate that tramadol potentiates the rewarding effects of morphine or buprenorphine largely in an additive manner and support the general contention that tramadol has relatively low abuse liability.     

The effect of analgesics on reflexes from the pericardium and the hilar region of the lungs during hypothermia

Summary The author studied the effect of morphine (2 and 5 mg/kg), promedol (1 and 3,5 mg/kg) and phenadone (1 mg/kg) on the reflex changes of the blood pressure after stimulating the pericardium and the area of the hilum of the lung at normal temperature and in hypothermia (30–32°C and 25–27°C).Experiments were performed on cats. Analgesics intensify the depressor vascular reflexes at normal temperatures; at lower temperatures this action is less pronounced. The change in the analgesic effect on the interoceptive reflexes from the thoracic organs in hypothermia should be regarded as the result of the altered functional condition of the central links in the reflex arc due to lowered body temperatures.Presented by Active Member AMN SSSR V. V. Zakusov     

The brief and the prolonged facilitatory effects of unmyelinated afferent input on the rat spinal cord are independently influenced by peripheral nerve section

Single C-fibre strength stimuli applied to the sciatic nerve in the decerebrate spinal rat evoke three separate bursts of activity in posterior biceps/semitendinosus flexor alpha motorneurones which are associated with the arrival in the spinal cord of volleys in the A-beta, A-delta and C-afferent fibres. Repetitive stimulation of the sciatic nerve at 1 Hz for 20 s generates a progressive wind-up of response and an after-discharge lasting up to 10 s. Twelve to fourteen days after section of the sciatic nerve, stimuli applied central to the section evoke a larger than normal response in the posterior biceps/semitendinosus flexor motorneurones and repetitive stimulation (1 Hz, 20 s) produces an after-discharge which is four times longer than that produced by stimulation of the intact nerve. In addition to the direct excitatory effects of sciatic nerve stimulation on the flexor motorneurones which lasts for seconds, conditioning stimuli to the sciatic nerve at C-fibre strength (1 Hz, 20 s) produce a facilitation of the flexor reflex evoked by a standard pressure stimulus to the ipsilateral and contralateral toes which lasts for 70 min. However, although the direct excitatory effects of stimulating a sectioned sciatic nerve on the posterior biceps/semitendinosus flexor motorneurones are exaggerated, the facilitation of the cutaneous flexion reflex evoked by stimulating sectioned sciatic nerves (1 Hz, 20 s) only lasts for 17 min. These results show that the mechanism which produces the rapid effects of sciatic nerve stimulation on the flexor reflex circuit can be separated from the mechanism which produces the prolonged facilitation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effect of intrathecal endomorphin-1 and endomorphin-2 on spinal cord excitability in rats

We examined and compared the effects of intrathecal (i.t.) endomorphin-1 and endomorphin-2 on the nociceptive flexor reflex in decerebrate, spinalized, unanesthetized rats. I.t. endomorphin-1 and -2 induced a dose-dependent depression of the flexor reflex with an initial brief facilitatory effect. The magnitude of reflex facilitation and depression was similar between endomorphin-1 and -2, but the duration of depression was significantly longer for endomorphin-1 than endomorphin-2. The results suggested that the spinal antinociceptive effects of endomorphin-1 and -2 are similar, with endomorphin-1 being more resistant to enzymatic degradation.     

Opioid modulation of reflex versus operant responses following stress in the rat

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.     

吗啡剂量及给药方式对大鼠运动敏感化的影响

目的:比较不同剂量吗啡皮下注射及给药方式(每日三次给药与每日一次给药)对Sprague-Dawlev大鼠运动敏感化的影响.方法:实验大鼠共分为五组,即生理盐水组、吗啡每日一次皮下注射组(1mg/kg组、3mg/kg组及10mg/kg组)以及吗啡每日三次皮下注射组(10mg/kg,次),每组8只大鼠.连续用药7天,隔日检测大鼠自发活动,然后停止药物处理,停药7天后每组大鼠予以吗啡3mg/kg皮下注射并检测大鼠自发活动.结果:吗啡每日一次皮下注射组中,各剂量组大鼠的运动敏感化均能顺利表达.吗啡每日三次皮下注射组大鼠的运动敏感化表达受到了抑制.结论:低剂量吗啡同样诱发运动敏感化,提示低剂量吗啡也会出现觅药动机敏感化,因此不要冒险尝试毒品即便是低剂量毒品;当每日一次间断用药时,运动敏感化更容易表达,提示负性强化可能是运动敏感化的调节机制之一.     

Sub-chronic administration of AM251, CB1 receptor antagonist,within the nucleus accumbens induced sensitization to morphine in the rat

It seems that there is a cross-talk between the cannabinoid CB1 and opioid receptors in the process of sensitization to opiates. In present study, we tried to examine the effect of solely administration of AM251, a CB1 receptor antagonist, on conditioned place preference (CPP) by ineffective dose of morphine in the rat. 102 adult male albino Wistar rats were used in these experiments. Subcutaneous administration of morphine (0.5, 1, 2.5, 5, 7.5 and 10 mg/kg) induced CPP only at the doses of ≥5 mg/kg. The dose of 0.5 mg/kg of morphine was selected as the appropriate (ineffective) dose for induction of CPP in animals which were previously received AM251 (5, 25 and 125 ng/0.5 μl per side) once daily for three days as a sub-chronic administration or those that received a single dose on the test day. Bilateral intra-accumbal sub-chronic but not single administration of AM251 dose-dependently produced sensitization to morphine and induced CPP by ineffective dose of morphine (0.5 mg/kg) in the rat. Bilateral intra-accumbal administration of neither saline nor DMSO (0.5 μl/side) had effects on sensitization to morphine. Our findings indicated that CB1 receptors within the nucleus accumbens are involved in the sensitization to morphine in rats.     

The role of the opioid receptor-like (ORL1) receptor in motor stimulatory and rewarding actions of buprenorphine and morphine

We have previously shown that the ability of buprenorphine to activate the opioid receptor-like (ORL1) receptor compromises its antinociceptive effect. Furthermore, morphine has been shown to alter the level of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the ORL1 receptor, raising the possibility that the endogenous OFQ/N/ORL1 receptor system may be involved in the actions of these opioids. Thus, using mice lacking the ORL1 receptor and their wild-type littermates, the present study assessed the role of the ORL1 receptor in psychomotor stimulant and rewarding actions of buprenorphine and morphine. Morphine (5, 10 mg/kg) dose-dependently increased motor activity and induced conditioned place preference. However, the magnitude of each response was comparable for the mutant mice and their wild-type littermates. In contrast, buprenorphine (1 mg/kg) induced greater motor stimulation in ORL1 receptor knockout mice as compared with their wild-type littermates. Further, single conditioning with buprenorphine (3 mg/kg) induced place preference in mutant mice but not in their wild-type littermates. The results of binding assay showed that buprenorphine concentration-dependently (0-1000 nM) displaced specific binding of [(3)H]-OFQ/N in brain membrane of wild-type mice. Together, the present results suggest that the ability of buprenorphine to interact with the ORL1 receptor modulates its acute motor stimulatory and rewarding effects.     

Effect of tonic voluntary activity on the excitability of human motor cortex.

1. The threshold for obtaining EMG responses after transcranial magnetic stimulation of the brain is reduced by voluntary contraction of the target muscle. The present experiments tested whether some of this effect is due to increased cortical, as opposed to spinal, excitability during the contraction. 2. Magnetic stimulation was delivered with a figure-of-eight coil oriented with the junction region along the interaural line and also (in 4 of 7 subjects) with a circular coil centred at the vertex. The intensity of the conditioning stimulus was subthreshold for evoking a motor response in the relaxed wrist flexor muscles of the forearm. The presence of a small descending corticospinal volley in both the relaxed and active conditions was detected by measuring the facilitation of test H reflexes elicited in the flexor muscles of the forearm. 3. In all subjects, magnetic stimulation with either coil facilitated the H reflex at conditioning-test intervals of -1 to -3 ms (median nerve stimulus before magnetic). This was followed by a long-lasting facilitation. In three of the seven subjects stimulation with the figure-of-eight coil elicited an additional, earlier peak of facilitation at a conditioning-test interval of -3 to -5 ms. 4. In all subjects, the threshold for obtaining facilitation of the H reflex using a conditioning-test interval of -1 to -3 ms was reduced, and the amount of facilitation was larger, if subjects performed a weak tonic voluntary contraction. In contrast, with a conditioning-test interval of -3 to -5 ms voluntary contraction had no effect on the threshold. 5. It is suggested that H reflex facilitation at the conditioning-test interval of -1 to -3 ms was produced by indirect activation of corticospinal neurones by the magnetic stimulus, whereas at -3 to -5 ms, the facilitation was produced by direct activation of corticospinal axons. It is concluded that tonic voluntary contraction of a target muscle decreases the threshold for indirect activation of corticospinal neurones but not for direct stimulation of their axons.     

Tachykinins mediate changes in spinal reflexes after activation of unmyelinated muscle afferents in the rat.

The effect of intrathecally applied tachykinin antagonist D-NicLys1, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.9, Nle11-substance P, spantide II, on the long-term increase of spinal cord excitability after activation of unmyelinated muscle afferents was studied in decerebrate, spinalized, unanaesthetized rats. A conditioning stimulus train (1 Hz, 20 s) that activated unmyelinated fibres in the gastrocnemius muscle nerve facilitated the flexor reflex for about 1 h, which was strongly blocked by pretreatment with spantide II (3 micrograms). The present results indicate that the facilitation of the flexor reflex by conditioning stimulation of a muscle nerve is mediated by tachykinins and possibly other neuropeptides which may be released from the central terminals of these unmyelinated afferents.     

Effects of acetylsalicylic acid and morphine on neurons of the rostral ventromedial medulla in rat

Morphine exerts its analgesic effect via the endogenous pain control system consisting of the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM). Acetylsalicylic acid (ASA) may also act via this system, but so far this has only been demonstrated for the inhibitory effect on the tail-flick reflex with extremely high doses (200-300 mg/kg). Both drugs show synergistic effects on PAG neurons in vitro. It is unclear whether this mechanism accounts for the well-known analgesic synergism of these drugs in vivo. Thus, the effects of ASA (30 mg/kg) and morphine on off- and on-cells in the RVM and the jaw-opening reflex (JOR) were investigated in anesthetized rats. Under morphine, off-cell activity increased (+34%), on-cell activity decreased (-98%) and the reflex was suppressed (-53%). ASA increased off-cell activity (+20%) and decreased the activity of on-cells (-52%). After preceding ASA administration, the effects of morphine on off- and on-cells and on the reflex did not alter statistically. The experiments document the modulatory effect of a clinically relevant dose of ASA on RVM cells. This effect resembles that of morphine. The results do not support the hypothesis of a mediation of the analgesic synergism of morphine and ASA by the PAG-RVM-network in vivo.     

Differential antinociceptive effects induced by a selective cyclooxygenase-2 inhibitor (SC-236) on dorsal horn neurons and spinal withdrawal reflexes in anesthetized spinal rats

The aim of present study was to examine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold (1.5xT, the intensity threshold) electrical stimuli with different frequencies (3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced inflammation and central sensitization. During normal conditions, the responses of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli (3 Hz, wind-up) were depressed by systemic administration of SC-236 as well as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both the WDR neurons and the simultaneously recorded SMUs after electrical stimuli with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms underlying the generation of the C-fiber mediated late responses and the after-discharges may be different. The enhanced responsiveness of both WDR neurons and SMUs to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia) in the BV experiments was apparently depressed by SC-236, but not its vehicle. For electrical stimulation, the enhanced late responses and after-discharges, but not early responses, of both the WDR neurons and the simultaneously recorded SMUs were markedly depressed only by SC-236. This indicates that different central pharmacological mechanisms underlie the generation of these enhanced early, late responses, and after-discharges during BV-induced inflammation. The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities of both spinal cord dorsal horn neuron and spinal withdrawal reflex during BV-induced sensitization, indicating that COX-2 plays an important role in the maintenance of central sensitization.     

Single opioid administration modifies gonadal steroids in both the CNS and plasma of male rats

While morphine remains one of the most widely used opioids for the treatment of painful conditions, other opioids are also commonly employed. Because of the interactions between opioids and gonadal hormones, in particular opioid-induced hypogonadism, this study investigated the effects of widely used opioids on plasma testosterone and estradiol levels and brain testosterone levels in male rats. Animals were s.c. injected with two concentrations of morphine (5 or 10 mg/kg), fentanyl (0.05 or 0.1 mg/kg), tramadol (10 or 40 mg/kg), buprenorphine (0.05 or 0.1 mg/kg) or saline (0.7 ml/kg). Four or 24 h after treatment, the rats were deeply anesthetized to collect blood samples from the abdominal aorta and to perfuse the brains with saline. Plasma and brain hormone levels were measured by radioimmunoassay. In rats studied 4 h after treatment, all the opioids except tramadol 10 mg/kg decreased plasma testosterone in comparison with saline administration. At the same time, plasma estradiol levels were lower than control in the groups treated with the low doses of morphine, tramadol and buprenorphine, while estradiol remained at control levels in the other groups. Twenty-four hours after treatment, plasma testosterone levels were different (higher) than control in the animals treated with the low doses of morphine, fentanyl and buprenorphine. Estradiol was lower than control in the low dose groups, while the high doses did not produce any changes with respect to control. Four hours after treatment, brain testosterone was drastically decreased in all groups except buprenorphine, in which it remained at control levels. All groups returned to control levels at 24 h after treatment. In conclusion, opioids exert important effects on plasma and CNS sex hormone levels. The different magnitude and time-course of the effects of the different opiates on testosterone and estradiol levels are likely due to their different mechanism of action.     

Effect of morphine on the adrenal sympathetic reflex elicited by mechanical stimulation of the skin in rats

The effect of morphine on the cutaneo-adrenal nerve reflex was studied in rats anesthetized with urethane-chloralose. Morphine (1 mg/kg, i.v.) significantly depressed the reflex increase in adrenal nerve activity induced by noxious lower chest pinching. Morphine (10 mg/kg, i.v.) significantly inhibited the reflex decrease in adrenal nerve activity induced by innocuous lower chest and hindlimb brushing, as well as the response induced by noxious lower chest pinching. Reversal by naloxone of the morphine-induced depression of the cutaneo-adrenal nerve reflexes indicates that the opioid receptor is associated with these effects of morphine.     

Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate-putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompanied by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate-putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate-putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.