Biomedical subjects

Antti Pertovaara

Publications and source records attributed to Antti Pertovaara.

At least 19 recordsLinked to original sources

PubMed2006

Noradrenergic pain modulation.

Norepinephrine is involved in intrinsic control of pain. Main sources of norepinephrine are sympathetic nerves peripherally and noradrenergic brainstem nuclei A1-A7 centrally. Peripheral norepinephrine has little influence on pain in healthy tissues, whereas in injured tissues it has variable effects, including aggravation of pain. Its peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ionic channel properties of primary afferent nociceptors, while an interaction with the immune system may contribute in part to peripheral antinociception induced by norepinephrine. In the spinal cord, norepinephrine released from descending pathways suppresses pain by inhibitory action on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct alpha-2-adrenergic action on pain-relay neurons (postsynaptic inhibition), and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Additionally, alpha-2C-adrenoceptors on axon terminals of excitatory interneurons of the spinal dorsal horn possibly contribute to spinal control of pain. At supraspinal levels, the pain modulatory effect by norepinephrine and noradrenergic receptors has varied depending on many factors such as the supraspinal site, the type of the adrenoceptor, the duration of the pain and pathophysiological condition. While in baseline conditions the noradrenergic system may have little effect, sustained pain induces noradrenergic feedback inhibition of pain. Noradrenergic systems may also contribute to top-down control of pain, such as induced by a change in the behavioral state. Following injury or inflammation, the central as well as peripheral noradrenergic system is subject to various plastic changes that influence its antinociceptive efficacy.

Adaptation, Physiological↗

PubMed2006

Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat.

Descending noradrenergic pathways contribute to feedback inhibition of pain by releasing norepinephrine in the spinal cord. Noradrenergic nuclei in the pons contain abundant alpha(2)-adrenoceptors. We assessed the contribution of pontine alpha(2)-adrenoceptors to endogenous regulation of pain in nerve-injured rats. Tactile allodynia and mechanical hyperalgesia were assessed in the injured dermatome and heat nociception in an uninjured dermatome. Atipamezole, an alpha(2)-adrenoceptor antagonist, or saline was administered systemically or microinjected into the locus coeruleus, the lateral parabrachial nucleus, the central nucleus of the amygdala, the midbrain periaqueductal gray, and/or through an intrathecal (i.t.) catheter to the spinal cord. Atipamezole administered systemically, into the amygdala or the periaqueductal gray had no significant effects on pain behavior. Atipamezole (0.3-5 microg) microinjected into the pons, the locus coeruleus or the lateral parabrachial nucleus, produced a selective and dose-related antiallodynia, which was reversed by i.t. administration of atipamezole (5 microg). I.t. administration of atipamezole alone (5 microg) produced thermal hypersensitivity in the non-neuropathic segment (tail) of nerve-injured animals. In sham-operated controls, i.t. administration of atipamezole had no effect. Suppression of heat nociception in uninjured dermatomes of nerve-injured but not the control animals following i.t. administration of atipamezole indicates that nerve injury produced a tonic activation of noradrenergic feedback inhibition acting on spinal alpha(2)-adrenoceptors. In parallel, antiallodynia induced by pontine administration of atipamezole indicates that nerve injury induces a tonic activation of pontine alpha(2)-adrenoceptors that promotes neuropathic hypersensitivity by attenuating descending inhibition. Thus, spinal and pontine alpha(2)-adrenoceptors have opposite effects on pain-related behavior in neuropathic animals.

Adrenergic alpha-Antagonists↗

PubMed2006

5-HT(1A) receptors in endogenous regulation of neuropathic hypersensitivity in the rat.

The role of medullary and spinal 5-HT(1A) receptors in endogenous regulation of neuropathic hypersensitivity was studied. When administered in the rostroventromedial medulla or subcutaneously, WAY-100635, a 5-HT(1A) receptor antagonist, attenuated mechanical hypersensitivity in rats with a spinal nerve injury. Thermal or mechanical nociception outside of the injured area was not influenced by medial medullary or subcutaneous administration of WAY-100635. Intrathecal administration of WAY-100635 had no significant effect on pain-related behavior. Suppression of mechanical hypersensitivity induced by medial medullary administration of WAY-100635 was reversed by intrathecal administration of WAY-100635 or atipamezole, an alpha2-adrenoceptor antagonist, but not by naloxone, an opioid receptor antagonist. The results indicate that endogenous release of 5-HT, via action on medial medullary 5-HT(1A) receptors, tonically suppresses descending inhibition in neuropathic animals. Following medial medullary administration of a 5-HT(1A) receptor antagonist, descending pain regulatory pathways are disinhibited. This leads to selective attenuation of neuropathic hypersensitivity, due to action on spinal 5-HT(1A) receptors and alpha2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed2006

Localization of touch versus heat pain in the human hand: a dissociative effect of temporal parameters on discriminative capacity and decision strategy.

We studied the influence of temporal parameters on localization of monofilament-evoked touch versus thulium laser-induced and C fiber-mediated pain in human subjects. Stimuli were applied at interstimulus intervals (ISIs) varying from 1 to 9 s to determine discrimination between successive stimulus sites in the palmar skin. Localization threshold was about two times higher for heat pain than touch. The localization threshold for pain, but not touch, decreased with prolongation of the ISI from 1 to 7-9 s, and it remained higher for pain even at the ISI of 9 s. The response time was longer for pain than touch, and it increased with an increase in the ISI, independent of the modality. Discriminative capacity, as assessed by the receiver operating characteristics curve, was markedly better for touch than pain. The discriminative capacity decreased with an increase of the ISI, but only for touch. The results indicate that localization is more accurate for touch than pain. Temporal summation of C fiber-evoked pain contributes to the reduced accuracy of pain localization if the ISI is < or = 3 s. Additionally, temporal factors dissociatively influence the response strategy in the tactile versus pain localization task with the prolongation of the ISI from 1 to 9 s. Due to this strategy change, localization threshold for touch remains constant at prolonged ISIs, in spite of a decrease in discriminative capacity. In a cutaneous localization task, the subject's accuracy and response strategy vary with the modality and temporal parameters of sequential test stimulation.

Adult↗

PubMed2005

Influence of the dopamine D2 receptor knockout on pain-related behavior in the mouse.

We studied the role of the dopamine D2 receptor in physiological regulation of pain-related behavior. The experiments were performed in dopamine D2 receptor knockout mice and in their wild-type controls. Baseline sensitivity to thermal nociception was determined by measuring the response latency in the hot plate at three different stimulus temperatures and by determining the radiant-heat-induced paw withdrawal. Mechanical sensitivity was assessed by determining paw withdrawal responses to stimulation with a calibrated series of monofilaments. Intracolonic capsaicin was used to produce sustained pain-related behavior and referred hypersensitivity to mechanical stimulation. The hot plate response latencies were not significantly different between the dopamine D2 receptor knockout and wild-type animals, although the stimulus temperature-dependent decrease in the response latency was steeper in the wild-type group. The radiant-heat-induced paw withdrawal latency was slightly longer in the knockout animals. The number of capsaicin-induced behavioral responses or the latency to the occurrence of the first capsaicin-induced response was not different between the experimental groups. Dopamine D2 receptor knockout animals were more sensitive to mechanical stimulation of the hindpaws than wild-type animals both in the baseline condition and following development of capsaicin-induced referred hypersensitivity in the hindpaws. The results indicate that dopamine D2 receptors influence baseline nociception in the mouse, although this effect is weak and submodality selective. Additionally, dopamine D2 receptors may contribute to attenuation of referred hypersensitivity caused by sustained nociception.

Animals↗

PubMed2005

Somatotopic blocking of sensation with navigated transcranial magnetic stimulation of the primary somatosensory cortex.

We demonstrate that spatially accurate and selective stimulation is crucial when cortical functions are studied by the creation of temporary lesions with transcranial magnetic stimulation (TMS). Previously, the interpretation of the TMS results has been hampered by inaccurate knowledge of the site and strength of the induced electric current in the brain. With a Navigated Brain Stimulation (NBS) system, which provides real-time magnetic resonance image (MRI)-guided targeting of the TMS-induced electric field, we found that TMS of a spatially restricted cortical S1 thenar area is sufficient to abolish sensation from a weak electric stimulation of the corresponding skin area. We demonstrate that with real-time navigation, TMS can be repeatably directed at millimeter-level precision to a target area defined on the MRI. The stimulation effect was temporally and spatially specific: the greatest inhibition of sensation occurred when TMS was applied 20 ms after the cutaneous test stimulus and the TMS effect was sensitive to 8-13 mm displacements of the induced electric field pattern. The results also indicate that TMS selectively to S1 is sufficient to abolish perception of cutaneous stimulation of the corresponding skin area.

Adult↗

PubMed2005

Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist.

Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. Unlike many other alpha2-adrenoceptor antagonists, it has negligible affinity for 5-HT1A and I2 binding sites. Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by alpha2-adrenoceptor agonists. Due to this property, atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by alpha2-adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, atipamezole increased pain-related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short-term working memory. At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.

Adrenergic alpha-Agonists↗

PubMed2004

Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia.

Striatal dopamine D2/D3 receptors have been suggested to play a role in pain sensitivity and placebo effect. We studied whether the association of dopamine D2/D3 receptor binding potential (BP) with sensory thresholds is specific to the modality of pain, and whether striatal dopamine D2/D3 receptor BP predicts the magnitude of placebo analgesia. Pain and tactile thresholds, and placebo analgesia were assessed in eight healthy human male subjects who had previously participated in a dopamine D2/D3 receptor positron emission tomography study with [11C]raclopride. The results show that the cutaneous heat pain threshold was inversely correlated with dopamine D2/D3 receptor BP in the right putamen, but responses to tactile stimulation did not correlate with striatal dopamine D2/D3 receptor BP. Placebo-induced elevation of the heat pain threshold did not correlate with striatal dopamine D2/D3 receptor BP. These results suggest that the influence of striatal dopamine D2/D3 receptors on sensory thresholds is selective for the modality of pain. Moreover, striatal dopamine D2/D3 receptor BP appears not to predict individual's analgesic response to placebo.

Adult↗

PubMed2004

Striatal dopamine D2 receptors in modulation of pain in humans: a review.

We review evidence indicating that the striatum and striatal dopamine D2 receptors are involved in the regulation of pain in humans. Painful stimulation produces an increase in regional cerebral blood flow in the human striatum. Pain is a common symptom in patients with nigrostriatal dopaminergic hypofunction. Positron emission tomography findings show that a low dopamine D2 receptor availability in the striatum of healthy subjects (indicating either a low density of dopamine D2 receptors or a high synaptic concentration of dopamine) is associated with a high cold pain threshold and a low capacity to recruit central pain inhibition by conditioning stimulation. Patients with chronic orofacial pain have higher dopamine D2 receptor availability than their age-matched controls. We propose that the striatal dopamine D2 receptor may be an important target for the diagnosis and treatment of chronic pain.

Animals↗

PubMed2004

Colorectal distension-induced suppression of a nociceptive somatic reflex response in the rat: modulation by tissue injury or inflammation.

Inhibition of somatic nociception by conditioning noxious visceral stimulation was studied under pathophysiological conditions in rats. Viscero-somatic inhibition was enhanced following visceral inflammation and reduced by a somatic heat injury. The enhancement was reversed by an N-methyl-D-aspartate (NMDA) receptor antagonist. These changes in viscero-somatic inhibition may be explained by corresponding changes in excitatory drives evoked by conditioning and test stimulation, although disinhibition may contribute to reduction of inhibition following somatic injury.

Animals↗

PubMed2004

Spatial integration of cold pressor pain sensation in humans.

Spatial integration of cold pressor pain (CPP) in the hand was studied in healthy human subjects by measuring the latency to the ice water-induced first pain sensation with and without conditioning CPP. CPP alone showed a marked spatial summation effect. When conditioning and test CPP were applied at the same time, conditioning CPP suppressed test CPP both in an adjacent and a distant site. When test CPP was applied after the conditioning CPP (i.e. pain induced by conditioning CPP was considerably stronger than that evoked by test CPP) conditioning CPP suppressed the test CPP only in a distant site but enhanced it in an adjacent site. A decrease in the test stimulus area increased the suppressive effect by conditioning CPP. Thus, CPP shows spatial summation or inhibition depending on experimental parameters.

Adult↗

PubMed2004

Prolactin-releasing peptide affects pain, allodynia and autonomic reflexes through medullary mechanisms.

Prolactin-releasing peptide (PrRP) and neuropeptide FF (NPFF) are RF-amide peptides expressed in brain areas involved in pain modulation. NPFF displays multiple effects on acute, inflammatory and neuropathic pain. The potential role of PrRP in pain was addressed by intrathecal and intracerebral injections of PrRP on pain-related responses in both neuropathic and normal rats. Particularly in the dorsal medulla, PrRP produced significant antinociception in normal rats and an antiallodynic effect in neuropathic rats. To understand the basis of PrRP-induced pain modulation, distributions of PrRP, PrRP receptor, and NPFF were compared in the rat central nervous system. PrRP and NPFF mRNA were expressed in different parts of the nucleus of the solitary tract. In the medulla, PrRP receptor mRNA expression was abundant only in area postrema. Of the peptides studied, only NPFF mRNA was found in the dorsal horn of the spinal cord and spinal nucleus of the trigeminal nerve. PrRP-immunoreactivity corresponded to the mRNA distribution. Even if the neuronal groups producing NPFF and PrRP were distinct, the fiber networks immunoreactive for PrRP and NPFF overlapped. The results show that PrRP modulates nociception due to supraspinal rather than spinal action, and that its antinociceptive mechanism differs from that previously characterized for NPFF.

Animals↗

PubMed2004

A potential aphrodisiac for female macaques.

Earlier studies suggest that alpha2-adrenoceptor antagonists and dopamine receptor agonists may enhance sexual activity in human and nonhuman male primates. It is not known whether these compounds influence the sexual behavior of female primates. We determined whether the administration of a selective alpha2-adrenoceptor antagonist (atipamezole), a dopamine receptor agonist (apomorphine), or their combination to female Macaca arctoides (stumptail macaque) monkeys produces changes in sexual behavior of the female with a male. Following the administration of drugs to the female, the behavior of the female with a male stumptail was observed for 30 min. Atipamezole dose dependently (0.03-0.3 mg/kg im) increased short-time mounting behavior of the male and the total number of copulations. Apomorphine alone (0.125-0.25 mg/kg) or in combination with atipamezole had no significant effects on sexual behavior. The result indicates that a selective alpha2-adrenoceptor antagonist administered in the female stumptail increases sexual behavior of the male with the female. A plausible explanation for this finding is that a selective alpha2-adrenoceptor antagonist increases sexual arousal in female stumptails and this, possibly due to a change in psychosocial behavior of the female, triggers increased sexual activity in males.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

The effect of interstimulus interval on somatosensory point localization.

Somatosensory point localization is a clinical test evaluating spatial accuracy of the somatosensory system. Possible effects of the interstimulus interval (ISI) on point localization threshold have not been previously examined. In the present set of experiments the effect of time delay on somatosensory point localization was studied using ISIs of 1, 3, 5, 7, and 9 s, and applying a newly developed computer-controlled application method of a Semmes-Weinstein monofilament. It was found that the point localization threshold was not significantly affected by the ISI length. However, the response time was shorter and response accuracy better at the shorter (1 and 3 s) than at the longer (5, 7, and 9 s) ISIs, suggesting a change in the mechanism underlying point localization decision criteria in ISIs longer than 3 s.

Adult↗

PubMed2004

Alpha(2A) adrenoceptors contribute to feedback inhibition of capsaicin-induced hyperalgesia.

BACKGROUND: Studies on receptor knockout mice have so far shown that of the three alpha2-adrenoceptor subtypes, the alpha(2A) adrenoceptor has a major role in mediating the powerful central analgesia induced by synthetic alpha2-adrenoceptor agonists. However, because a knockout of the gene for the alpha(2A) adrenoceptor has produced only little if any change in the pain sensitivity of control, nerve-injured, or inflamed animals, it has not been clear whether activation of alpha(2A)-adrenoceptors by endogenous ligands has a significant pain regulatory role. METHODS: The authors assessed spontaneous pain behavior and mechanical hypersensitivity induced by administration of capsaicin in the colon or paw of alpha(2A)-adrenoceptor knockout mice versus their wild-type controls. RESULTS: Enhanced pain hypersensitivity was observed in alpha(2A)-adrenoceptor knockout mice 20 min or more after administration of capsaicin, but before, hypersensitivity and spontaneous pain were of equal magnitude in alpha(2A)-adrenoceptor knockout and wild-type mice. When wild-type mice were pretreated with an alpha2-adrenoceptor antagonist, capsaicin-induced pain hypersensitivity increased to a level equal to that in alpha(2A)-adrenoceptor knockout mice. Capsaicin-induced hypersensitivity was suppressed in wild-type but not alpha(2A)-adrenoceptor knockout mice by a centrally acting alpha2-adrenoceptor agonist, whereas a peripherally acting alpha2-adrenoceptor agonist was without effect on hypersensitivity, although it attenuated capsaicin-induced spontaneous pain behavior in wild-type mice. CONCLUSIONS: This study shows that central alpha(2A)-adrenoceptors contribute to feedback inhibition of pain hypersensitivity. Also, alpha(2A)-adrenoceptors are critical for not only somatic but also visceral antinociceptive effects induced by synthetic alpha2-adrenoceptor agonists.

Administration, Rectal↗

PubMed2004

Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain.

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [(11)C]raclopride in the striatum (n = 8) and with [(11)C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subject's discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subject's response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subject's response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subject's attitude towards pain than by a dopaminergic effect on the subject's discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus-response function for sensory signals, mimicking a change in the subject's response criterion.

Adult↗

PubMed2004

Antinociceptive properties of fadolmidine (MPV-2426), a novel alpha2-adrenoceptor agonist.

Fadolmidine (MPV-2426) is a novel alpha2 -adrenoceptor (alpha2) -AR) agonist developed for spinal analgesia. It is highly selective for alpha2 -ARs, but it lacks subtype selectivity. Due to its pharmacokinetic properties, it only poorly penetrates blood-brain barrier or spreads from the site of injection within the central nervous system. By intrathecal (i.t.) administration to laboratory animals, fadolmidine produces dose-dependent antinociception in healthy controls and in models of inflammatory, postoperative and neuropathic pain. Fadolmidine has been effective against various submodalities of pain such as heat pain, mechanical pain, and visceral pain. In general, the antinociceptive potency of fadolmidine, i.t., was equal to that of dexmedetomidine. At antinociceptive i.t. doses fadolmidine did not suppress motoneurons or responses to innocuous stimulation. It produced no hemodynamic depression and considerably less sedation than dexmedetomidine. By peripheral administration fadolmidine had no or only a weak antinociceptive action, except following nerve injury, particularly that of the postganglionic sympathetic nerve fibers. Together these experimental animal studies indicate that i.t. administration of fadolmidine provides a segmentally restricted treatment of somatic and visceral pain, with only minor cardiovascular and sedative side effects. Additionally, peripheral administration of fadolmidine might provide a selective treatment for some hypersensitivity states that involve dysfunction of the sympathetic nervous system.

Adrenergic Agonists↗

PubMed2003

The alpha2A-adrenoceptor subtype is not involved in inflammatory hyperalgesia or morphine-induced antinociception.

The purpose of the present study was to investigate the role of the alpha(2A)-adrenoceptor subtype in inflammatory hyperalgesia, and in adrenergic-mu-opioid interactions in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and thermal stimuli were studied in alpha(2A)-adrenoceptor knockout mice and their wild-type controls. Thermal nociception was evaluated as paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured using von Frey monofilament applications to the hindpaws. Mechanical and thermal hyperalgesia, induced with intraplantar carrageenan (1 mg/40 microl) were compared in alpha(2A)-adrenoceptor knockout and wild-type mice. The effects of the systemically administered mu-opioid receptor agonist morphine (1-10 mg/kg) were evaluated on mechanical withdrawal responses under normal and inflammatory conditions in knockout and wild-type mice. Withdrawal responses to radiant heat and von Frey monofilaments were similar in alpha(2A)-adrenoceptor knockout and wild-type mice before and after the carrageenan-induced hindpaw inflammation. Also, the antinociceptive effects of morphine in mechanical nociceptive tests were similar before and after carrageenan-induced hindpaw inflammation. Our observations indicate that alpha(2A)-adrenoceptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia. In addition, alpha(2A)-adrenoceptors do not appear to play an important role in mu-opioid receptor-mediated antinociception or antihyperalgesia.

Analgesia↗