Gregory W. Terman

Opioid and non-opioid stress analgesia from cold water swim: importance of stress severity

We have previously reported that stress severity plays an important role in determining the neurochemical basis of stress-induced analgesia from inescapable footshock. Increasing severity (duration or intensity of continuous footshock) causes a shift in mediation of the resultant analgesia from opioid to non-opioid. In this study, we find that stress severity plays a similar role in analgesia from cold water swim. More severe swims (longer duration or lower water temperature) produce stress analgesia insensitive to the opiate antagonist, naltrexone, whereas less severe swims produce analgesia significantly attenuated by this drug.

Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth

Exposure to stress has been associated with alterations in both immune function and tumor development in man and laboratory animals. In the present study, we investigated the effect of a particular type of inescapable footshock stress, known to cause an opioid mediated form of analgesia, on survival time of female Fischer 344 rats injected with a mammary ascites tumor. Rats subjected to inescapable footshock manifested an enhanced tumor growth indicated by a decreased survival time and decreased percent survival. This tumor enhancing effect of stress was prevented by the opiate antagonist, naltrexone, suggesting a role for endogenous opioid peptides in this process. In the absence of stress, naltrexone did not affect tumor growth.

Postoperative opioid-induced respiratory depression: a closed claims analysis.

Background:Postoperative opioid-induced respiratory depression (RD) is a significant cause of death and brain damage in the perioperative period. The authors examined anesthesia closed malpractice claims associated with RD to determine whether patterns of injuries could guide preventative strategies. Methods:From the Anesthesia Closed Claims Project database of 9,799 claims, three authors reviewed 357 acute pain claims that occurred between 1990 and 2009 for the likelihood of RD using literature-based criteria. Previously cited patient risk factors for RD, clinical management, nursing assessments, and timing of events were abstracted from claim narratives to identify recurrent patterns. Results:RD was judged as possible, probable, or definite in 92 claims (&kgr; = 0.690) of which 77% resulted in severe brain damage or death. The vast majority of RD events (88%) occurred within 24 h of surgery, and 97% were judged as preventable with better monitoring and response. Contributing and potentially actionable factors included multiple prescribers (33%), concurrent administration of nonopioid sedating medications (34%), and inadequate nursing assessments or response (31%). The time between the last nursing check and the discovery of a patient with RD was within 2 h in 42% and within 15 min in 16% of claims. Somnolence was noted in 62% of patients before the event. Conclusions:This claims review supports a growing consensus that opioid-related adverse events are multifactorial and potentially preventable with improvements in assessment of sedation level, monitoring of oxygenation and ventilation, and early response and intervention, particularly within the first 24 h postoperatively.

Neuropathic Pain Activates the Endogenous κ Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [κ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the κ agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.

L-type calcium channels mediate dynorphin neuropeptide release from dendrites but not axons of hippocampal granule cells

Granule cells in the guinea pig dentate gyrus release kappa opioid neuropeptides, dynorphins, from dendrites as well as from axon terminals. We have found that both L- and N-type calcium channel antagonists inhibited dendritic dynorphin release. In contrast, N-type but not L-type calcium channel antagonists inhibited axonal dynorphin release. Neither L- nor N-type channel antagonists directly altered the effects of kappa opioid receptor activation. By inhibiting dynorphin release, L-type channel antagonists also facilitated the induction of long-term potentiation of the perforant path-granule cell synapse. These studies establish that a single cell type can release a transmitter from two different cellular domains and provide new distinction between axonal and dendritic transmitter release mechanisms.

Analgesic, locomotor and lethal effects of morphine in the mouse: strain comparisons.

We have compared the analgesic, locomotor stimulatory and lethal effects of morphine in two strains of mice, C57BL/6BY and CXBK. The CXBK strain is known to be deficient in central opioid binding sites and to be less sensitive than the C57 strain to certain effects of morphine and endogenous opioids. We found that the CXBK strain was less sensitive than the C57s to the analgesic and locomotor effects of morphine, but did not significantly differ in regard to morphines lethal effect. The strain differences in sensitivity to the analgesic and locomotor effects were not uniform. The CXBK strain was much less sensitive than the C57 strain to the analgesic effect but only moderately less sensitive to the locomotor stimulatory effect. These differences may relate to previously demonstrated strain differences in the amounts of mu 1 and mu 2 opioid binding in central nervous system areas thought to mediate these behaviors.

G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal

Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G‐protein receptor kinase mediated receptor phosphorylation and subsequent β‐arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G‐protein receptor kinase 3 (GRK3) gene. Mice lacking GRK3 did not differ from wild‐type littermates neither in their response latencies to noxious stimuli on the hot‐plate test nor in their acute antinociceptive responses to fentanyl or morphine. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild‐type littermate controls. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3‐mediated desensitization. The results of these studies suggest that GRK3‐mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3‐dependent effects than morphine, a low efficacy agonist.

Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance

Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats.

TrkB Activation by Brain-derived Neurotrophic Factor Inhibits the G Protein-gated Inward Rectifier Kir3 by Tyrosine Phosphorylation of the Channel

G protein-activated inwardly rectifying potassium channels (Kir3) are widely expressed throughout the brain, and regulation of their activity modifies neuronal excitability and synaptic transmission. In this study, we show that the neurotrophin brain-derived neurotrophic factor (BDNF), through activation of TrkB receptors, strongly inhibited the basal activity of Kir3. This inhibition was subunit dependent as functional homomeric channels of either Kir3.1 or Kir3.4 were significantly inhibited, whereas homomeric channels composed of Kir3.2 were insensitive. The general tyrosine kinase inhibitors genistein, Gö 6976, and K252a but not the serine/threonine kinase inhibitor staurosporine blocked the BDNF-induced inhibition of the channel. BDNF was also found to directly stimulate channel phosphorylation because Kir3.1 immunoprecipitated from BDNF-stimulated cells showed enhanced labeling by anti-phosphotyrosine-specific antibodies. The BDNF effect required specific tyrosine residues in the amino terminus of Kir3.1 and Kir3.4 channels. Mutations of either Tyr-12, Tyr-67, or both in Kir3.1 or mutation of either Tyr-32, Tyr-53, or both of Kir3.4 channels to phenylalanine significantly blocked the BDNF-induced inhibition. The insensitive Kir3.2 was made sensitive to BDNF by adding a tyrosine (D41Y) and a lysine (P32K) upstream to generate a phosphorylation site motif analogous to that present in Kir3.4. These results suggest that neurotrophin activation of TrkB receptors may physiologically control neuronal excitability by direct tyrosine phosphorylation of the Kir3.1 and Kir3.4 subunits of G protein-gated inwardly rectifying potassium channels.

Stress-induced analgesia in the mouse: strain comparisons

&NA; Inescapable footshock is capable of differentially activating opioid‐ and nonopioid‐mediated mechanisms of stress‐induced analgesia in the rat, depending on the temporal and intensive parameters of its administration. In this study we compared the effects of opioid and non‐opioid stress analgesia in two strains of mice, one known to be deficient in central opioid binding sites (CXBK) and one normal in this regard (C57BL/6BY). We found that although the C57 strain showed robust opioid and non‐opioid stress analgesia, the CXBK strain only showed stress analgesia of the non‐opioid type.