Biomedical subjects

T Philip Malan

Publications and source records attributed to T Philip Malan.

15 recordsLinked to original sources

PubMed2006

CB2 cannabinoid receptor mediation of antinociception.

Management of acute pain remains a significant clinical problem. In preclinical studies, CB2 cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB2 receptor-selective agonist AM1241 produces antinociceptive effects that are antagonized by CB2, but not CB1, receptor-selective antagonists, suggesting that activation of CB2 receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB2 receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB1 and CB2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB2-like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM1241 and the less-selective CB2 receptor agonist WIN55,212-2 in wild-type (CB2+/+) mice and in mice with genetic disruption of the CB2 receptor (CB2-/- mice). AM1241 inhibited thermal nociception in CB2+/+ mice, but had no effect in CB2-/- littermates. WIN55,212-2 produced equivalent antinociception in CB1+/+ and CB1-/- mice, while its antinociceptive effects were reduced in CB2-/- compared to CB2+/+ mice. The effects of morphine were not altered in CB2-/- compared to CB2+/+ mice. These data strongly suggest that AM1241 produces antinociception in vivo by activating CB2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB2 cannabinoid receptors for the treatment of acute pain.

Analgesics↗

PubMed2005

CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.

CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB(2) receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB(2) receptor activation stimulates release from keratinocytes of the endogenous opioid beta-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB(2) receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to beta-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that beta-endorphin is necessary for CB(2) receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in mu-opioid receptor-deficient mice. Hindpaw injection of beta-endorphin was sufficient to produce antinociception. AM1241 stimulated beta-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB(2) cannabinoid receptor-selective antagonist and was not observed in skin from CB(2) cannabinoid receptor-deficient mice. These data suggest that CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB(2) immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.

Analgesics↗

PubMed2005

Lipid mediators regulating pain sensitivity.

The papers in this symposium demonstrate that lipid molecules are ubiquitous messengers that participate in intracellular signaling, function in intercellular communication, and serve as neurotransmitters. This review examines the contribution of lipid messengers in regulating a specific physiological function, the transmission of noxious sensory information (pain) in the nervous system. Lipid molecules play major roles in the modulation of pain sensitivity. Six types of lipid molecules (prostanoids, phosphatidyl inositol bisphosphate, ceramide, lipoxygenase metabolites of arachidonic acid, fatty acyl dopamines, and acylethanolamides) have been shown to modulate systems important in the regulation of pain responses. These molecules exert their actions by interacting with varied receptor systems. Evidence for their participation in the regulation of pain responses comes from in vitro demonstrations of their interactions with signaling systems known to be important in the regulation of pain sensitivity and, in some cases, from demonstration of their ability to modulate pain sensitivity after in vivo administration. One of these classes of lipid mediators, the acylethanolamides, inhibits pain responses, while the others appear to enhance pain sensitivity. Given the rapid growth in our understanding of lipidomics, evident in the papers of this issue, it is virtually certain that additional lipid mediators will be identified as being central to the regulation of pain responses.

Animals↗

PubMed2005

The cyclooxygenase-2-specific inhibitor parecoxib sodium is as effective as 12 mg of morphine administered intramuscularly for treating pain after gynecologic laparotomy surgery.

Parecoxib sodium, the injectable prodrug of valdecoxib, is a cyclooxygenase-2-specific inhibitor that is effective in the treatment of postoperative pain. In this randomized, double-blind, placebo-controlled study, we compared the efficacy of a single dose of parecoxib sodium 40 mg IM with single doses of morphine 6 and 12 mg IM in treating postoperative pain after gynecologic surgery requiring a laparotomy incision. By nearly all efficacy measures (including total pain relief and patient's global evaluation of study medication), parecoxib sodium 40 mg IM demonstrated pain relief and a decrease in pain intensity that was statistically similar to that with morphine 12 mg IM and superior to that with morphine 6 mg IM. Parecoxib sodium 40 mg IM-treated patients also demonstrated a longer time to use of rescue medication than patients treated with both morphine doses, and this dose provided sustained pain relief over the 12-h study period. The incidence of adverse events in the active treatment groups was similar to that observed with placebo. Parecoxib sodium, 40 mg IM, has been shown to be as effective as clinically relevant doses of morphine in patients after gynecologic laparotomy surgery.

Adult↗

PubMed2004

Antinociceptive and nociceptive actions of opioids.

Although the opioids are the principal treatment options for moderate to severe pain, their use is also associated with the development of tolerance, defined as the progressive need for higher doses to achieve a constant analgesic effect. The mechanisms which underlie this phenomenon remain unclear. Recent studies revealed that cholecystokinin (CCK) is upregulated in the rostral ventromedial medulla (RVM) during persistent opioid exposure. CCK is both antiopioid and pronociceptive, and activates descending pain facilitation mechanisms from the RVM enhancing nociceptive transmission at the spinal cord and promoting hyperalgesia. The neuroplastic changes elicited by opioid exposure reflect adaptive changes to promote increased pain transmission and consequent diminished antinociception (i.e., tolerance).

Analgesics↗

PubMed2004

Differential blockade of nerve injury-induced thermal and tactile hypersensitivity by systemically administered brain-penetrating and peripherally restricted local anesthetics.

UNLABELLED: Systemic administration of local anesthetics has been shown to transiently reverse thermal and tactile hypersensitivity induced by peripheral nerve injury, effects that have been taken as suggesting direct actions on the peripheral nerves. The present study sought to determine whether a central site of action could contribute to, or account for, the effects of lidocaine on nerve injury-induced thermal and tactile hypersensitivity. Systemic lidocaine and its peripherally restricted analogues, QX-314 or QX-222, effectively reversed thermal hypersensitivity after spinal nerve ligation injury. Nerve injury-induced tactile hypersensitivity, however, was reversed by systemic lidocaine but not QX-314 or QX-222. Microinjection of either lidocaine or QX-314 into the rostral ventromedial medulla fully reversed spinal nerve ligation-induced thermal and tactile hypersensitivity. The data strongly suggest that nerve injury-induced thermal and tactile hypersensitivity are mediated through different mechanisms. In addition, the present study supports a prominent contribution of the central nervous system in the activity of systemically given lidocaine against nerve injury-induced tactile and thermal hypersensitivity. Thus, lidocaine might reverse tactile hypersensitivity mainly through its actions within the central nervous system, whereas its reversal of thermal hypersensitivity might occur through either central or peripheral sites. PERSPECTIVE: Nerve injury-induced neuropathic pain has proved remarkably difficult to treat. Systemic administration of ion channel blockers such as lidocaine has been explored for the management of chronic pain. This work indicates that systemic rather than local administration of lidocaine would be more effective in treating tactile allodynia.

Anesthetics, Local↗

PubMed2004

Production of paradoxical sensory hypersensitivity by alpha 2-adrenoreceptor agonists.

BACKGROUND: Administration of opioid receptor agonists is followed by paradoxical sensory hypersensitivity. This hypersensitivity has been suggested to contribute to the antinociceptive tolerance observed with opioids. The authors hypothesized that alpha 2-adrenoreceptor agonists, which also produce antinociceptive tolerance, would produce sensory hypersensitivity. METHODS: alpha 2-Adrenoreceptor agonists were administered to male Sprague-Dawley rats as a single subcutaneous injection, a continuous subcutaneous infusion, a single intrathecal injection, or a continuous intrathecal infusion. Thermal sensitivity was determined using latency to withdrawal of the hind paw from radiant heat. Tactile sensitivity was determined using withdrawal threshold to von Frey filaments. Spinal dynorphin content was measured by enzyme immunoassay. RESULTS: Single systemic or intrathecal injections of clonidine or dexmedetomidine produced antinociception followed by delayed thermal and tactile hypersensitivity. Six-day systemic or intrathecal infusion of clonidine produced tactile and thermal hypersensitivity observed even during clonidine infusion. Sensory hypersensitivity was prevented by coadministration of the alpha 2-adrenoreceptor-selective antagonist idazoxan or the N-methyl-D-aspartate receptor-selective antagonist MK-801. Six-day infusion of intrathecal clonidine increased dynorphin content in dorsal lumbar spinal cord. MK-801 and dynorphin antiserum reversed clonidine-induced sensory hypersensitivity. CONCLUSIONS: alpha 2-Adrenoreceptor agonists produce sensory hypersensitivity that may be analogous to that produced by opioids. Sensory hypersensitivity was prevented by idazoxan, demonstrating that it is mediated by alpha 2 receptors. Clonidine infusion increased spinal dynorphin content. Sensory hypersensitivity was prevented or reversed by MK-801 and dynorphin antiserum, implicating N-methyl-D-aspartate receptors and spinal dynorphin in its production. Clinicians should be mindful of the possibility of drug-induced hyperalgesia in patients treated with alpha 2-adrenoreceptor agonists.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2003

Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS.

We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1-/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.

Analgesics↗

PubMed2003

CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?

Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB(2) (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.

Analgesics↗

PubMed2003

Parecoxib sodium, a parenteral cyclooxygenase 2 selective inhibitor, improves morphine analgesia and is opioid-sparing following total hip arthroplasty.

BACKGROUND: This study examined the opioid-sparing effectiveness, analgesic efficacy, and tolerability of postoperative administration of the parenteral cyclooxygenase 2 selective inhibitor, parecoxib sodium, in total hip arthroplasty patients. METHODS: This was a multicenter, multiple-dose, randomized, double-blind, placebo-controlled study to compare the opioid-sparing effects, analgesic efficacy, and tolerability of postoperative 20 and 40 mg intravenous parecoxib sodium with placebo in hip arthroplasty patients. The first dose of study medication was administered after surgery with an intravenous bolus dose of 4 mg morphine when patients first requested pain medication; remedication with the study medication occurred at 12 and 24 h. Subsequent morphine doses (1-2 mg) were administered by patient-controlled analgesia. Efficacy was assessed by total morphine used, pain relief and pain intensity, time to last dose of morphine, and Global Evaluation rating of the study medication. RESULTS: Parecoxib sodium, 20 and 40 mg, reduced the total amount of morphine required over 36 h by 22.1% (56.5 mg morphine) and 40.5% (43.1 mg morphine), respectively, compared with placebo (72.5 mg morphine; P < 0.01). Patients receiving 20 and 40 mg parecoxib sodium experienced significantly greater maximum pain relief compared with those in the placebo group (P < 0.05). Patients who received 20 and 40 mg parecoxib sodium discontinued PCA morphine earlier than patients receiving placebo and had significantly higher Global Evaluation ratings. Parecoxib sodium, 40 mg, plus morphine demonstrated a significantly lower incidence of fever and vomiting compared with placebo plus morphine. CONCLUSIONS: Administration of parecoxib sodium with PCA morphine resulted in significantly improved postoperative analgesic management as defined by reduction in opioid requirement, lower pain scores, reduced time on PCA morphine, and higher Global Evaluation ratings.

Aged↗

PubMed2003

Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors.

BACKGROUND: Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia. METHODS: Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251. RESULTS: AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection. CONCLUSIONS: Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.

Analgesics↗

PubMed2002

Inhibition of pain responses by activation of CB(2) cannabinoid receptors.

Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB(1) cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB(2) cannabinoid receptor-selective agonists has allowed testing whether CB(2) receptor activation inhibits pain. CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB(1) receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects.

Animals↗

PubMed2002

Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers.

Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin. Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7. The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRP. Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin antiserum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.

Animals↗

PubMed2002

Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.

Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. Tactile and thermal hypersensitivity were induced in rats by spinal nerve ligation (SNL). RVM lidocaine blocked SNL-induced tactile and thermal hypersensitivity on post-SNL days 6-12 but not on post-SNL day 3. Lesion of RVM cells expressing mu-opioid receptors with dermorphin-saporin did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Similarly, lesions of the dorsolateral funiculus (DLF) did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Lesions of the DLF also blocked the SNL-induced increase in spinal dynorphin content, which has been suggested to promote neuropathic pain. These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states.

Animals↗

PubMed2002

Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain.

BACKGROUND: This study tests the hypothesis that loss of spinal activity of gamma-aminobutyric acid (GABA) contributes to the allodynia and hyperalgesia observed after peripheral nerve injury. METHODS: Intrathecal catheters were implanted in male Sprague-Dawley rats. Antinociception was assessed by measuring withdrawal latency to immersion of the tail in a 52 degrees C water bath. Nerve injury was produced by ligation of the L5 and L6 spinal nerves. Testing was performed 4-14 days after spinal nerve ligation, when tactile allodynia and thermal hyperalgesia were established. Tactile allodynia was quantitated using the threshold to withdrawal of the hind paw on probing with von Frey filaments. Thermal hyperalgesia was quantitated using the latency to withdrawal of the hind paw from radiant heat. Motor function was tested using a rotarod apparatus. RESULTS: Spinal administration of the GABAA receptor antagonist bicuculline or the GABAB receptor antagonist phaclofen produced tactile allodynia and thermal hyperalgesia in normal rats. The GABAB receptor agonist baclofen, administered spinally, produced antinociception in the tail-flick test, whereas the GABAA receptor agonist isoguvacine did not. Isoguvacine and baclofen each reversed tactile allodynia and thermal hyperalgesia produced by spinal nerve ligation. Baclofen but not isoguvacine prolonged thermal withdrawal latency in nerve-injured rats beyond preoperative values. Baclofen but not isoguvacine impaired motor function. CONCLUSIONS: Pharmacologic inhibition of intrinsic GABA tone in normal rats resulted in tactile allodynia and thermal hyperalgesia, consistent with the hypothesis being tested. Exogenous administration of GABA agonists reversed spinal nerve ligation-induced allodynia and hyperalgesia, also consistent with this hypothesis. Isoguvacine produced specific antihyperalgesic and antiallodynic effects, whereas assessment of the effects of baclofen was complicated by motor dysfunction. Spinal GABAA agonists may provide a specific therapy for neuropathic pain.

Animals↗