Long-lasting antinociceptive effects of green light in acute and chronic pain in rats.

Treatments for chronic pain are inadequate, and new options are needed. Nonpharmaceutical approaches are especially attractive with many potential advantages including safety. Light therapy has been suggested to be beneficial in certain medical conditions such as depression, but this approach remains to be explored for modulation of pain.

Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids.

Background: Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain.

A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.

Unlabelled: Postherpetic neuralgia (PHN) is a painful complication of acute herpes zoster. This multicenter, double-blind, controlled study randomized 299 PHN patients to receive either NGX-4010, a high-concentration capsaicin (8%) patch, or a low-concentration capsaicin (0.04%) control patch for 30, 60, or 90 minutes.

NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.

Objectives: To assess the efficacy, tolerability, and safety of NGX-4010, a high-concentration capsaicin dermal patch (capsaicin 640 microg/cm(2), 8%) in patients with postherpetic neuralgia (PHN).

Methods: Patients were randomized to receive NGX-4010 or control patch in a 4-week, double-blind study. This was followed by an open-label extension phase (up to 48 weeks total) where patients could receive up to three additional treatments no sooner than 12 weeks after initial treatment.

NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study.

Background: The limitations of current treatments for postherpetic neuralgia (PHN) have led to the investigation of localised, non-systemic alternatives. NGX-4010, a high-concentration (8%) capsaicin dermal patch, was developed to treat patients with neuropathic pain. We report the results of a randomised, double blind, 12-week study of the efficacy and safety of one application of NGX-4010 in patients with PHN.

Supporting the academic mission in an era of constrained resources: approaches at the University of Arizona College of Medicine.

The authors describe initiatives at the University of Arizona College of Medicine to markedly expand faculty, build research along programmatic lines, and promote a new, highly integrated medical school curriculum. Accomplishing these goals in this era of declining resources is challenging. The authors describe their approaches and outcomes to date, derived from a solid theoretical framework in the management literature, to (1) support research faculty recruitment, emphasizing return on investment, by using net present value to guide formulation of recruitment packages, (2) stimulate efficiency and growth through incentive plans, by using utility theory to optimize incentive plan design, (3) distribute resources to support programmatic growth, by allocating research space and recruitment dollars to maximize joint hires between units with shared interests, and (4) distribute resources from central administration to encourage medical student teaching, by aligning state dollars to support a new integrated organ-system based-curriculum.

Phoenix rises, with Tucson's help: establishing the first four-year allopathic program in the nation's fifth largest city.

The authors describe the expansion of The University of Arizona College of Medicine from Tucson, Arizona, into Phoenix. They explain how the new Phoenix program, in partnership with Arizona State University, is one college of medicine for the state of Arizona, governed by a single accreditation by the Liaison Committee for Medical Education (LCME). The authors present 21 lessons to be considered early in a medical school expansion process: clearly establish responsibility, authority, and accountability; define activities under university purview and those that require broader engagement; delineate college-wide versus campus-specific functions; clearly define the intent of the new initiative; get frequent input from the LCME; use LCME input to ensure a student focus; be cautious in using consultants; use respected local "brokers"; create a single locus for input and concerns; educate constituencies about medical school requirements; engage leadership to create linkages across sites; encourage communication between leaders in both sites; discriminate between shared and distinctive local curriculum elements; consider the effort and experience required to develop a full curriculum versus those required to develop specific local curricular areas; create simple, transparent admission processes; define faculty profiles for the new program; ensure sufficient resources for core faculty; budget based on national metrics; create core mission-based principles to frame discussions and decisions; segregate clinical affiliation discussions from curriculum and recruitment of basic science faculty; and ensure sufficient land.

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.

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.

Role of NK-1 neurotransmission in opioid-induced hyperalgesia.

Opiates are among the most important drugs for treatment of moderate to severe pain and prolonged opiate administration is often required to treat chronic pain states. We investigated the neurobiological actions of sustained opiate administration revealing paradoxical pronociceptive adaptations associated with NK-1 receptor function. Sustained morphine delivered over 6 days elicited hyperalgesia in rats and mice during the period of opiate delivery.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

CB2 cannabinoid receptor-mediated peripheral antinociception.

Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB(1) receptor in the production of antinociception. However, the capacity of CB(2) receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known.