Effects of the novel BK (KCa 1.1) channel opener GoSlo-SR-5-130 are dependent on the presence of BKß subunits.

BACKGROUND AND PURPOSE: GoSlo-SR compounds are efficacious BK (KCa 1.1) channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. EXPERIMENTAL APPROACH: A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BKα alone or in combination with either ß1 or ß4 subunits. KEY RESULTS: GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2 ) of BK channels approximately -100 mV, irrespective of the presence of regulatory ß subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by approximately -100 mV; however, this was reduced by ∼80% in HEK cells expressing only BKα subunits. When ß1 or ß4 subunits were co-expressed with BKα, efficacy was restored. GoSlo-SR-5-130 caused a concentration-dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels. CONCLUSIONS AND IMPLICATIONS: GoSlo-SR-5-130 required ß1 or ß4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of ß subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. The novel BK channel opener, GoSlo-SR-5-130, is approximately fivefold more efficacious on BK channels with regulatory ß subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder.

Patient-controlled analgesia using ropivacaine via an intrathecal catheter.

BACKGROUND AND OBJECTIVES: A 38-year-old woman presented with severe intractable pain in the sacral and perirectal areas secondary to metastatic stage I.B. squamous cell carcinoma of the cervix. METHODS: An indwelling epidural catheter was placed to control the patient's symptoms after failure of conservative therapies. Finally, an infusion containing isobaric 0.2% ropivacaine with 0.002% preservative-free morphine and 0.0002% epinephrine was started to treat her pain and preserve motor function to preserve quality of life. RESULTS: The patient obtained good pain relief with this regimen and was discharged home. She was able to walk with assistance and maintain good quality of life until her death approximately 7 weeks after the placement of the indwelling epidural catheter. CONCLUSION: The use of ropivacaine in combination with other analgesics, via an intrathecal catheter for patient-controlled analgesia, was an effective treatment for this patient. In the future, ropivacaine administered epidurally or intrathecally alone, or in combination with other analgesics, may become the local anesthetic of choice due to its preservation of motor function. Certainly, further scientific studies are indicated in the cancer patient population.

Cholinomimetics, but not morphine, increase antinociceptive behavior from pontine reticular regions regulating rapid-eye-movement sleep.

Sleep disruption is a significant problem associated with the subjective experience of pain. Both rapid-eye-movement (REM) sleep and nociception are modulated by cholinergic neurotransmission, and this study tested the hypothesis that antinociceptive behavior can be evoked cholinergically from medial pontine reticular formation (mPRF) regions known to regulate REM sleep. The foregoing hypothesis was investigated by quantifying the effect of mPRF drug administration on tail flick latency (TFL) of cat during polygraphically defined sleep/wake states. The mPRF was microinjected with 0.25 ml saline, carbachol (4.0 microg), neostigmine (6.7 microg), or morphine sulfate (14.7 microg), and TFL measures were obtained in response to radiant heat. During wakefulness TFL (% increase) was not increased by morphine or saline, but was significantly increased by mPRF administration of carbachol (42.4%) and neostigmine (35.2%). Cortical somatosensory potentials (SSEPs) were reliably evoked by tail stimulation before and after mPRF microinjections of carbachol. The results show for the first time that mPRF administration of cholinomimetics significantly increased TFL. During NREM sleep and REM sleep, TFL was significantly increased compared to waking TFL (110% and 321%, respectively). The finding of sleep-dependent alterations in TFL demonstrates that mPRF regions known to regulate REM sleep can modulate supraspinal cholinergic antinociceptive behavior.

Adrenocorticotropic hormone infusion as a novel treatment for postdural puncture headache.

BACKGROUND AND OBJECTIVES: In two patients, one scheduled for epidural anesthesia and the other for placement of a spinal catheter for operative procedures, severe postdural puncture headache developed and was refractory to conservative therapy. METHODS: The first patient had several unintentional dural punctures, and the second underwent a planned dural puncture with an 18-gauge needle for insertion of a 20-gauge catheter. When neither patient responded to conservative therapy following development of postdural puncture headache, an infusion of adrenocorticotropic hormone (ACTH) was given prior to consideration of epidural blood patching. RESULTS: Both patients obtained complete and permanent relief from their headaches. CONCLUSION: A single treatment with ACTH may offer an alternative therapy in the treatment of postdural puncture headache.