Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat

Earlier studies indicate that striatal dopamine D(2) receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D(2) receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D(2) receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D(2) receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D(2) receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D(2) receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D(2) receptors.     

Roles of capsaicin-sensitive primary afferents in differential rat models of inflammatory pain: a systematic comparative study in conscious rats

To characterize the role of capsaicin-sensitive primary afferents in inflammatory pain, the effects of subcutaneous (s.c.) injection of 0.15% capsaicin on different chemical irritants-induced pathological nociception including persistent spontaneous nociception, primary thermal and mechanical hyperalgesia, and inflammatory response were systematically investigated in unanesthetized conscious rats. Four different animal models of inflammatory pain: the bee venom (BV) test, the formalin test, the carrageenan model, and the complete Freund's adjuvant (CFA) model, were employed and compared. Local pre-treatment with capsaicin produced a significant inhibition on the s.c. BV and formalin induced long-lasting persistent spontaneous nociception. However, this capsaicin-induced inhibitory effect on spontaneous nociception in the BV test was only found within the late phase (tonic nociception; 11-60 min), but not the early phase (acute nociception; 0-10 min). A complete preventing effect of capsaicin on the decreased thermal paw withdrawal latency was found in the BV, carrageenan, and CFA models. Nevertheless, pre-treatment with capsaicin only produced complete blocking effects on the decreased mechanical paw withdrawal threshold in the BV and carrageenan models, but not in the CFA model. For inflammatory response, a significant inhibition of the BV-elicited paw swelling was found following capsaicin treatment. In marked contrast, capsaicin did not produce any effects on the paw inflammation during exposure to carrageenan, CFA, and formalin. These data suggest that capsaicin-sensitive primary afferents may play differential roles in the induction and development of pathological nociception in differential inflammatory pain models. In contrast to other chemical irritants, BV-induced long-term spontaneous nociception, facilitated nociceptive behavior, and inflammation are modulated by peripheral capsaicin-sensitive afferents.     

Stimulation of the periaqueductal gray matter of the rat produces a preferential ipsilateral antinociception.

The few studies analyzing somatotopic organization of stimulation-produced antinociception (SPA) from the periaqueductal gray matter (PAG) have reported contradictory results. In the present study, the distribution of SPA on the hindquarters was assessed by measuring the threshold for inhibition of withdrawal reflexes to noxious heat applied to the hindpaws and tail in pentobarbital-anesthetized rats. Of the 3 body regions tested, the hindpaw contralateral to the stimulating electrode required the highest level of PAG stimulation to inhibit withdrawal. Reducing the intensity of the heat stimulus applied to the hindpaws caused a concomitant reduction in SPA threshold. As before, a higher stimulation current was needed to inhibit the withdrawal reflex in the contralateral than in the ipsilateral paw. These data indicate the antinociception from PAG stimulation is not equally distributed throughout the body, and that the intensity of the noxious stimulus influences the threshold for SPA.     

Stress-induced analgesia in μ-opioid receptor knockout mice reveals normal function of the δ-opioid receptor system

Stress-induced analgesia (SIA) was examined in wildtype and μ-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20°C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective δ-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact δ-receptor-mediated function of a physiologically-released endogenous agonist in the μ-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice.     

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.     

Blocking mu opioid receptors in the spinal cord prevents the analgesic action by subsequent systemic opioids

Systemically administered mu opioids may produce analgesia through inhibition of the ascending nociceptive transmission and activation of descending pathways. However, the relative importance of the spinal and supraspinal sites in the analgesic action of systemic opioids remains uncertain. It has been shown that systemic morphine can inhibit dorsal horn neurons independent of the descending system. In this study, we determined the extent to which spinal mu opioid receptors mediate the analgesic effect of systemic mu opioids. Rats were instrumented with an intrathecal catheter with the tip placed in the lumbar spinal cord. Nociception was measured by testing the paw withdrawal threshold in response to a noxious radiant heat or pressure stimulus. Surprisingly, intrathecal pretreatment with naloxone or H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP, a specific mu opioid receptor antagonist) completely blocked the inhibitory effect of intravenous morphine on mechanical nociception. Intrathecal naloxone or CTAP also abolished the effect of intravenous morphine on the withdrawal latency of the hindpaw, but not the forepaw, measured with a radiant heat stimulus. Furthermore, the inhibitory effect of subcutaneous fentanyl on mechanical nociception was eliminated by CTAP injected intrathecally. Intrathecal CTAP similarly abolished the effect of subcutaneous fentanyl on thermal nociception of the hindpaw but not the forepaw. Therefore, this study provides new information that when spinal mu opioid receptors are blocked, subsequent systemic administration of mu opioids fails to produce an analgesic effect. This finding highlights the important role of mu opioid receptors in the spinal cord in the antinociceptive action of opioids.     

Intense peripheral electrical stimulation evokes brief and persistent inhibition of the nociceptive tail withdrawal reflex in the rat

In a study of modulation of nociception by sensory inputs, electrical stimulation was applied to specific sites in the hindlimb and effects on the nociceptive tail withdrawal reflex were monitored in the lightly anaesthetized rat. Stimulation was applied to previously defined sites in the hindlimb, meridian points femur-futu (ST-32), fengshi (GB-31) and zusanli (ST-36). It consisted of a 4 Hz train of 2 ms square pulses given for 20 min at 20 × the threshold intensity required for muscle twitch. Tail withdrawal was provoked by application of a noxious heat stimulus applied to the tip of the tail. Results were expressed as a percentage of the maximal possible inhibition which is achieved when the post-treatment latency is 2 × the pre-treatment latency otherwise known as the cut off. During stimulation, the latency of the withdrawal increased to ≈ 70% of the maximal possible inhibition. Following stimulation, the inhibition persisted for > 1 h. Stimulation at 2 or 6 Hz elicited similar effects but stimulation at 8 Hz evoked inhibition during the stimulation only. Stimulation applied to sites away from defined meridian points inhibited tail withdrawal during the stimulation; no post-stimulation effect was produced. In acutely transected animals (≤ 48 h), stimulation of meridian points elicited a small, brief increase in latency but during stimulation only. At 7 and 14 days after spinal transection, this response during stimulation was greater in magnitude and a brief post-stimulation increase was also observed. The return of the of this latter effect was coincident with the return of bladder function. These data suggest that high intensity, low frequency electrical stimulation of hindlimb meridian points in the lightly anaesthetized rat produces both brief and persistent inhibitory effects on the nociceptive tail withdrawal reflex. These effects appear to be elicited by different mechanisms. The persistent effect may represent a plastic change in central inhibitory mechanisms. Data from spinal animals indicate a major participation of supraspinal structures but that spinal mechanisms are also capable of sustaining both types of effect.     

Tuberoinfundibular peptide of 39 residues decreases pain-related affective behavior

Tuberoinfundibular peptide of 39 residues (TIP39) is a recently identified parathyroid hormone 2 receptor ligand. Their CNS distributions suggest potential involvement in neuroendocrine, limbic and sensory processing functions. Herein we investigate the analgesic and antinociceptive actions of brain delivery of TIP39 in adult male rats. Intracerebroventricular (i.c.v.) TIP39 did not change hot-plate paw withdrawal latency or formalin test behavioral responses. TIP39 partially reversed tactile withdrawal hypersensitivity following carageenan administration. In the place/escape avoidance paradigm (PEAP), which evaluates affective components of responses to noxious stimuli by presenting a choice between a naturally preferred environment paired with stimulation of a carrageenan sensitized paw and a less preferred environment paired with stimulation of a less sensitive paw, TIP39 decreased the apparent aversiveness of sensitive paw stimulation. Because acute sensory thresholds were unaffected by TIP39, and the effects of i.c.v. TIP39 were opposite in direction from previously described effects of intrathecal TIP39, this suggests that TIP39 may modulate an affective component of nociception within the brain.     

Spinalization increases the mechanical stimulation-induced withdrawal reflex threshold after a sciatic cut in the rat

The purpose of the present study was to establish whether supraspinal structures modulate mechanical ‘adjacent hyperalgesia'. After a chronic sciatic cut, the paw withdrawal threshold to mechanical stimulation was lower, and the latency of noxious radiant heat-induced withdrawal reflex was shorter at the traumatized side than at the intact side. Then the rats were spinalized, and the withdrawal threshold to mechanical stimulus increased at the injured side, but the withdrawal latency induced by noxious heat decreased at the intact side. No side differences between the injured and the intact side could be detected after spinalization. Thus supraspinal structures may participate in maintenance of mechanically evoked paw withdrawal reflex after a sciatic injury.     

Pivotal involvement of neurogenic mechanism in subcutaneous bee venom-induced inflammation and allodynia in unanesthetized conscious rats

The bee venom (BV) model is a valid inflammatory pain model in animals and has been extended to human studies using its principle protein, mellitin. After subcutaneous (s.c.) injection of BV, long-lasting spontaneous nociception followed by thermal hyperalgesia, static allodynia, and local inflammatory response (edema) can be observed in rats. We hypothesize that (1) neurogenic components may contribute to the BV-induced inflammatory response and (2) static and dynamic mechanical allodynia may exist simultaneously in the BV model. Using different approaches including sciatic nerve transection (SCT), L4-L6 dorsal rhizotomy (DRT) and local treatment of the sciatic nerve with capsaicin, we found that SCT, DRT, and local capsaicin onto the sciatic nerve produced a significant inhibition of the BV-induced increase in volume of the injected paw, with a stronger effect of the SCT and the local capsaicin treatments than that of the DRT treatment. Static and dynamic mechanical allodynia in the BV test was assessed by measuring the paw withdrawal mechanical threshold and the paw withdrawal latency before and after the BV injection, respectively. Local capsaicin onto the sciatic nerve produced a significant inhibition of the BV-induced decrease in the paw withdrawal mechanical threshold, but not the paw withdrawal latency, of the injected paw. These findings suggest that neurogenic components, via dorsal root reflex and axon reflex mechanisms, are probably involved in the maintenance and the development of the BV-induced inflammation. In addition, the capsaicin-sensitive primary afferents may play differential roles in the development of the BV-induced static and dynamic mechanical allodynia.     

Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain

Previous studies suggest that dopamine in the nucleus accumbens links noxious or mesolimbic stimulation with the feedback inhibition of nociception. To test the hypothesis that pharmacological agonism at dopamine receptors in the nucleus accumbens elicits antinociception, we bilaterally microinjected dopamine D1- and D2-receptor subtype selective drugs, and then evaluated behavioral responses to noxious intraplantar formalin. While the D1-selective agonist SKF 38393 was without effect at a dose of 0.5 nmol/side, the D2-selective agonist quinpirole dose-dependently (0.05-5.0 nmol/side, bilateral) inhibited the persistent phase of formalin-induced nociception. This was blocked by pre-administration of a selective D2-dopaminergic antagonist raclopride (0.3 nmol/side, bilateral). Quinpirole did not produce overt behavioral effects and did not change rotarod latency. Our results indicate that quinpirole acts at dopamine D2 receptors in the nucleus accumbens to inhibit persistent nociception at doses that circumvent confounding non-specific motor deficits, namely, sedation and motor coordination.     

Unilateral subcutaneous bee venom but not formalin injection causes contralateral hypersensitized wind-up and after-discharge of the spinal withdrawal reflex in anesthetized spinal rats

This study aimed to investigate the effect of tonic nociception on spinal withdrawal reflexes including (1) long lasting spontaneous responses elicited by subcutaneous (s.c.) administration of formalin (2.5%, 50 microl) and bee venom (BV, 0.2 mg/50 microl) into the hind paw and (2) corresponding ipsilateral (primary) and contralateral (secondary) hypersensitivity to noxious pinch and repetitive supra-threshold (1.5 x T) electrical stimuli at different frequencies (3 Hz: wind-up; 20 Hz: after-discharge) in anesthetized spinal rats. Spinal withdrawal reflexes were studied by simultaneously assessing single motor units (SMUs) electromyographic (EMG) activities from the bilateral medial gastrocnemius (MG) muscles. Subcutaneous formalin-induced persistent spontaneous SMU EMG responses were in typical biphasic manner with an apparent silent period (about 13-18 min), but in contrast, BV elicited monophasic long lasting (about 1 h) SMU EMG responses without any resting state. The mechanically and electrically evoked responsiveness of SMUs were enhanced significantly by ipsilateral BV injection, whereas enhanced electrically, but not mechanically, evoked responses (including wind-up and after-discharge) were found at the non-injection site of the contralateral hind paw. However, s.c. administration of formalin was only able to establish ipsilateral hypersensitivity of the SMUs to repeated electrical, not mechanical, stimulation. Neither mechanically nor electrically evoked contralateral hypersensitivity of the SMUs was found during the ipsilateral formalin-induced nociception. For pharmacological intervention, intrathecal administration of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist CNQX (40 nmol/10 microl), but not the non-competitive NMDA receptor antagonist MK-801 (40 nmol/10 microl), significantly depressed BV-induced contralateral hypersensitivity of the SMUs to repeated 3 Hz (wind-up) and 20 Hz (after-discharge) frequencies of electrical stimulation. Using the extracellular SMU recording technique, we found that s.c. administration of formalin and BV shows a significant difference in long lasting spontaneous firing of SMUs. This is consistent with previous observations in animal behavioral studies. Additionally, contralateral electrically evoked hypersensitivity of the SMUs was found only following BV injection, not in the formalin test. The maintenance and development of BV-induced contralateral hypersensitivity of the spinal withdrawal reflex to noxious electrical stimulation indeed depend on different central pharmacological receptors. The spinal non-NMDA, but not the NMDA, receptors may play important role in BV-induced contralateral central hyperexcitability and sensitization.     

The D2 receptor is critical in mediating opiate motivation only in opiate-dependent and withdrawn mice

According to the dual systems model for opiate reward, dopamine mediates opiate motivation when an animal is in a deprived motivational state (i.e. opiate-dependent and in withdrawal) and not when an animal is in a nondeprived state (i.e. previously drug-naive). To determine the role of the D2 dopamine receptor subtype in mediating opiate motivation, we examined the behaviour of N5 congenic D2 receptor knockout mice and their wild-type siblings in opiate-naive and opiate-dependent and withdrawn place conditioning paradigms. Opiate-naive D2 receptor knockout mice demonstrated acquisition of morphine-conditioned place preference but failed to acquire place preference when conditioned in the deprived state. We propose that D2 receptor function is critical in mediating the motivational effects of opiates only when the animal is in an opiate-dependent and withdrawn motivational state. These findings also underscore the important influence of the genetic background to a given phenotype, as evidenced by the observation that increasing the allelic contribution from the 129/SvJ strain abolishes morphine place preference in C57BL/6 wild-type mice.     

Decreased L5 spinal nerve ligation nociceptive behavior following L4 spinal nerve transection

This study used the escape/avoidance paradigm to explore the role of the L4 spinal nerve in L5 ligation nociception. Unlike L5-ligated controls, L5-ligated/L4-transected animals had normal mechanical withdrawal threshold and did not escape/avoid mechanical stimulation of the afflicted paw. The result from the escape/avoidance paradigm, which does not rely on a reflexive withdrawal response, directly supports the hypothesis that the L4 spinal nerve contributes to L5 ligation neuropathic pain.     

Region specific increase of dopamine receptor D1/D2 mRNA expression in the brain of mu-opioid receptor knockout mice

Previous pharmacological studies have indicated the possible existence of functional interactions between opioidergic and dopaminergic neurons in the CNS. In this study, the expression of mRNAs encoding dopamine receptor D1/D2 was examined to investigate whether there is a change in the dopamine pathway of mice lacking the mu-opioid receptor by in situ hybridization technique. In the mu-opioid receptor knockout mice, the expression of dopamine receptor D1 mRNA was increased in the olfactory tubercle, nucleus accumbens, caudate putamen, and the layer VI of the neocortex compared with that of wild-type mice. The expression of dopamine receptor D2 mRNA was also increased in the olfactory tubercle, caudate putamen, and the nucleus accumbens of mu-opioid receptor knockout mice. These results indicate that there are compensational changes in the dopaminergic systems of mu-opioid receptor knockout mice.     

Region specific increase of dopamine receptor D1/D2 mRNA expression in the brain of μ-opioid receptor knockout mice

Previous pharmacological studies have indicated the possible existence of functional interactions between opioidergic and dopaminergic neurons in the CNS. In this study, the expression of mRNAs encoding dopamine receptor D1/D2 was examined to investigate whether there is a change in the dopamine pathway of mice lacking the μ-opioid receptor by in situ hybridization technique. In the μ-opioid receptor knockout mice, the expression of dopamine receptor D1 mRNA was increased in the olfactory tubercle, nucleus accumbens, caudate putamen, and the layer VI of the neocortex compared with that of wild-type mice. The expression of dopamine receptor D2 mRNA was also increased in the olfactory tubercle, caudate putamen, and the nucleus accumbens of μ-opioid receptor knockout mice. These results indicate that there are compensational changes in the dopaminergic systems of μ-opioid receptor knockout mice.     

Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice

Mice that incorporate the dopamine D1 receptor transgene controlled by the D1 receptor promoter exhibit a marked increase of D1 binding in several extra-striatal brain regions and show a paradoxical hypokinetic response to D1 agonist [Exp. Neurol. 157 (1999) 169]. The agonist-induced locomotor behavior of D1 receptor transgenic mice is similar to baseline locomotor activity manifested by D2 receptor deficient mice [J. Neurosci. 18 (1998) 3470]. The similarity between these two behavioral phenotypes raised the possibility that stimulation of the over-expressed D1 receptors in the transgenic mice could cause a suppression of D2 receptor responses that manifest in hypokinesia. Alternatively, the similar phenotypes could result from altered D1/D2 receptor balance in both animal models. Two different approaches were undertaken to test these alternative hypotheses. (1) The effects of pharmacological blockade of D2 receptors on D1 agonist-stimulated hypokinesia of the D1 over-expressing animals were investigated. (2) The behavioral phenotype of hybrid D1 receptor over-expressing/D2 receptor deficient mice generated by crossbreeding the D2 knockout mice and the D1 transgenic animals was studied. The results of these studies suggested that the hypomotor response of the D1 transgenic mice was not a result of an interaction of the over-expressed D1 receptors with the native D2 receptors and that over-expressed D1 receptors likely mediate hypokinesia in the D1 transgenic animals. Considering the significance of the D1 dopamine receptor as a therapeutic target for Parkinson's disease, this D1 receptor over-expressing model provides an important experimental system to probe the basis for altered behavioral responses following stimulation of transgenetically up-regulated receptors.     

Intrathecal administration of sigma-1 receptor agonists facilitates nociception: involvement of a protein kinase C-dependent pathway

Sigma sites, originally proposed as opioid receptor subtypes, are currently thought to represent unique receptors with a specific pattern of drug selectivity, a well-established anatomical distribution and broad range of functional roles including potential involvement in nociceptive mechanisms. We have recently demonstrated that intrathecal (i.t.) treatment with a sigma-1 receptor antagonist reduced formalin-induced pain behavior. In the present study, we investigated the potential role of spinal sigma-1 receptor agonists in peripherally initiated nociception and attempted to elucidate intracellular signaling mechanisms associated with spinal cord sigma-1 receptor activation in mice. The i.t. injection of the sigma-1 receptor agonists PRE-084 (PRE) or carbetapentane (CAR) significantly decreased tail-flick latency (TFL) and increased the frequency of paw withdrawal responses to mechanical stimulation (von Frey filament, 0.6 g) as well as the amount of Fos expression in the spinal cord dorsal horn induced by noxious paw-pinch stimulation. These PRE- or CAR-induced facilitatory effects on nociception were significantly blocked by i.t. pretreatment with the sigma-1 receptor antagonist, BD-1047, the phospholipase C (PLC) inhibitor, U-73,122, the Ca(2+)-ATPase inhibitor, thapsigargin, and the protein kinase C (PKC) inhibitor, chelerythrine. Western blot analysis further revealed that i.t. PRE or CAR injection significantly increased pan-PKC as well as the PKCalpha, epsilon, and zeta isoforms in the dorsal horn. Collectively, these findings demonstrate that calcium-dependent second messenger cascades including PKC are involved in the facilitation of nociception associated with spinal sigma-1 receptor activation.     

Blunted brain metabolic response to ketamine in mice lacking D(1A) dopamine receptors

The interaction of glutamatergic and dopamine neurotransmission is thought to have relevance to both the pathophysiology and pharmacotherapy of schizophrenia. For example, subanesthetic doses of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine induce schizophrenia-like behavioral effects in humans and both behavioral and brain metabolic activation in rodents. Blockade of NMDA-R results in dopamine release, and antipsychotic drugs that block dopamine neurotransmission decrease NMDA-R antagonist-induced behavioral activation. The involvement of dopamine receptors in brain metabolic activation induced by ketamine is, however, unknown. The present study used D(1A) knockout mice to determine the role of dopamine D(1A) receptors in the effects of subanesthetic doses of ketamine on both behavioral responses and on alterations in regional [14C]2-deoxyglucose (2-DG) uptake. There was less ketamine-induced behavioral activation in D(1A) knockout mice than in wild-type mice. In wild-type mice, ketamine (30 mg/kg) induced dramatic increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, basolateral amygdala, and caudal parts of the substantia nigra pars reticulata. D(1A) knockout mice exhibited blunted metabolic activation in response to ketamine in a neuroanatomically specific manner. The selective D(1) antagonist, SCH23390 (0.3 mg/kg), inhibited both ketamine-induced brain metabolic activation and behavioral responses in the wild-type mice, with a similar neuroanatomical specificity observed in the D(1A) knockout mice. Thus, the neuroanatomically selective role that D(1A) receptors play in ketamine-induced behavior and regional brain metabolic activation in mice provides a useful model for further studies of how the D(1A) receptor function may be altered in schizophrenia.     

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.