Neonatal bladder inflammation alters activity of adult rat spinal visceral nociceptive neurons.

PURPOSE: This investigation examined the effect of inflammation produced by intravesical zymosan during the neonatal period on spinal dorsal horn neuronal responses to urinary bladder distension (UBD) as adults. METHODS: Female rat pups (P14-P16) were treated with intravesical zymosan or with anesthesia-only. These groups of rats were subdivided forming four groups: half received intravesical zymosan as adults and half received anesthesia-only. One day later, rats were anesthetized, the spinal cord was transected at a cervical level and extracellular single-unit recordings of L6-S1 dorsal horn neurons were obtained. Neurons were classified as Type I--inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II--not inhibited by HNCS--and were characterized for Spontaneous Activity and responses to graded UBD (20-60 mm Hg). RESULTS: 227 spinal dorsal horn neurons excited by UBD were characterized. In rats treated as neonates with anesthesia-only, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following adult intravesical zymosan treatment whereas Type I neurons demonstrated decreased spontaneous and UBD-evoked activity relative to controls. In rats treated as neonates with intravesical zymosan, the spontaneous and UBD-evoked activity of both Type I and Type II neurons increased following adult intravesical zymosan treatment relative to controls. CONCLUSIONS: Neonatal bladder inflammation alters subsequent effects of acute bladder inflammation on spinal dorsal horn neurons excited by UBD such that overall there is greater sensory neuron activation. This may explain the visceral hypersensitivity noted in this model system and suggest that impaired inhibitory systems may be responsible.

Acute bladder inflammation differentially affects rat spinal visceral nociceptive neurons.

The present investigation examined the effect of inflammation produced by intravesical zymosan on spinal dorsal horn neuronal responses to urinary bladder distension (UBD). Extracellular single-unit recordings of neurons excited by UBD were obtained in spinalized female Sprague-Dawley rats. Neurons were classified as Type I-inhibited by heterotopic noxious conditioning stimuli (HNCS) or as Type II-not inhibited by a HNCS. In Experiment 1-following neuronal characterization, 1% zymosan was infused into the bladder and after 2h spinal units were recharacterized. Control rats received intravesical saline or subcutaneous zymosan. In Experiment 2-rats were pretreated with intravesical zymosan 24h prior to surgical preparation. Control rats received anesthesia only. 137 spinal dorsal horn neurons excited by UBD were characterized. In comparison with controls, Type II neurons demonstrated increased spontaneous and UBD-evoked activity following intravesical zymosan treatment (both Experiments 1 and 2) whereas Type I neurons demonstrated either no change (Experiment 1) or decreased activity (Experiment 2) following bladder inflammation. No significant changes were noted in neuronal activity in control experiments. Inflammation differentially affects subpopulations of spinal dorsal horn neurons excited by UBD that can be differentiated according to the effect of HNCS. This results in an altered pattern of spinal sensory transmission that may serve as the mechanism for the generation of visceral nociception.

Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats.

This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

Visceral nociceptive input to the area of the medullary lateral reticular nucleus ascends in the lateral spinal cord.

In halothane-anesthetized rats, neurons stereotaxically located in the region of the medullary lateral reticular nucleus (LRN) and responsive to urinary bladder distension (UBD) were characterized using extracellular electrodes. Most neurons excited by UBD were also excited by noxious stimuli applied to bilateral receptive fields comprising at least half of the body surface. These bilateral nociceptive specific (bNS) neurons exhibited graded responses to graded intensities of UBD. Neuronal responses to noxious UBD were highly positively correlated with responses to noxious colorectal distension, suggesting a convergence of visceral sensory information in the area of LRN. Bilateral lateral mid-cervical spinal cord lesions virtually abolished activity of bNS neurons evoked by noxious UBD, while dorsal midline lesions had no significant effect. These data support a role for neurons in the region of the LRN in visceral nociception and implicate traditional lateral spinal cord pain pathways in the transmission of visceral information to caudal ventrolateral medullary structures.

Effects of smoking on neuropathic pain in two people with spinal cord injury.

BACKGROUND/OBJECTIVE: To describe an apparent relationship between smoking and the neuropathic pain experience in people with spinal cord injury (SCI). METHOD: Case Reports. PARTICIPANTS/METHODS: Two individuals treated at a rehabilitation center. The first was a 38-year-old white man with a T1 2 SCI, American Spinal Injury Association (ASIA) impairment scale (AIS) A, secondary to motor vehicle crash. Duration of injury was 14 years. He reported burning pain in his legs, and has smoked 1/2 pack per day for the last 15 years. The second was a 55-year-old African American man with a T6 SCI, AIS A, secondary to gunshot wound. Duration of injury was 22 years. He was a 40-year 1/2 to 1 pack per day smoker, who, after injury, consistently experienced burning, radicular pain, rated 7/10, around the level of the injury. SUMMARY: The first subject rated his pain as 4/10 when not smoking and 7/10 when smoking. The pain subsided 30 minutes after smoking was discontinued. He noted an immediate increase in neuropathic pain when smoking. The second subject quit smoking for 1 month and immediately noted that the pain disappeared, rating it 0/10. After he resumed smoking, his radicular pain was 8.5/10 in the morning and 5/10 in afternoon. CONCLUSIONS: No similar reports have been published, based on a MEDLINE search. Nicotinic receptors have been implicated in pain perception. It is unclear to what extent these 2 cases generalize to the SCI population. We plan to explore this via survey and experimental research. Smoking cessation may have a dual benefit of increased health and decreased neuropathic pain.

Long-term use of gabapentin for treatment of pain after traumatic spinal cord injury.

OBJECTIVE: To determine the long-term efficacy of gabapentin as a treatment of pain after spinal cord injury. DESIGN: All patients with traumatic-onset spinal cord injury treated with gabapentin were identified and followed up using a longitudinal observational design with two contact points (6 and 36 months after the trial) using a semi-structured interview. The first follow-up interview attempted to capture all 31 patients placed on therapeutic trial. The second follow-up interview attempted to capture those reporting a favorable response (n = 14) to the therapeutic trial at the first follow-up. RESULTS: Of the 27 patients contacted at the first follow-up (87% response rate), 6 (22%) discontinued the trial secondary to intolerable side effects; therefore, the pain analgesic effects of gabapentin in these patients could not be determined. Of the remaining 21 patients, 14 (67%) reported a favorable response (i.e., a 2 or greater point reduction on a 0-10 pain-rating scale). The second follow-up interview captured 11 (79% response rate) of the 14 patients reporting a favorable response at the first interview, and 91% (10 of 11 patients) continued to report that gabapentin was an effective analgesic. There was no evidence to suggest dosing difficulties due to tolerance over the 3-year period. Sedation, dizziness, and forgetfulness were the most common side effects. CONCLUSIONS: Gabapentin may be an effective treatment of pain after spinal cord injury among those able to tolerate initial and long-term side effects.

Pain classification following spinal cord injury: the utility of verbal descriptors.

OBJECTIVES: To determine the predictive utility of verbal descriptors to distinguish between pain types following spinal cord injury (SCI). DESIGN: Cross-sectional. SETTING: USA. METHODS: Participants (n=29) completed the Short Form - McGill Pain Questionnaire (SF-MPQ) for each pain site reported. A total of 64 pain sites were reported with 80% of the sample reporting multiple pain sites. Each pain site was categorized using three different SCI pain classification schemes. The predictive utility of verbal descriptors to distinguish between pain types was examined statistically using (1) each word separately, (2) a combination of words (ie, the SF-MPQ total subscales, the number of words chosen on each scale), and (3) discriminant function analysis. RESULTS: There was a substantial overlap in the use of verbal descriptors across pain types. Few differences across pain types were found for endorsement of individual words, and differences across pain types were not found for any of the word combination scores. The majority of the verbal descriptors did not enter the step-wise discriminant functions for each SCI pain classification scheme, however, 'tingling' and 'aching' showed modest predictive utility for neuropathic and musculoskeletal pain, respectively. Correct classification was in the low range (ie, 39% to 82%, average=60%, with a 33% chance level). All three pain classification schemes showed the same general pattern of results. CONCLUSION: In general, verbal descriptors alone offered marginal utility with regard to identifying specific pain types following SCI. Future directions alone and implications are discussed.

Evidence for two populations of rat spinal dorsal horn neurons excited by urinary bladder distension.

Spinal L6-S2 dorsal horn neurons of cervical spinal cord-transected, decerebrate female rats were characterized using urinary bladder distension (UBD) as a visceral stimulus. Constant pressure, phasic, graded (20-80 mm Hg, 20 s) air UBD was delivered via a transurethral catether and extracellular single-unit recordings obtained from all neurons excited by UBD. Responses to graded UBD and noxious/non-noxious cutaneous stimuli were determined in 258 neurons which could be stratified into two groups based on their effect of a counterirritation stimulus: Type I neurons (n=112) were inhibited by noxious pinch presented in a non-segmental field; Type II neurons (n=146) were not similarly inhibited. Both Types of neurons were identified in both superficial and deep recording sites and demonstrated graded responses to graded UBD. All UBD-excited neurons had convergent cutaneous receptive fields (RFs) excited by non-noxious and/or noxious stimuli. As a group, Type I neurons had a period of decreased activity following termination of the distending stimulus whereas Type II neurons typically had a sustained afterdischarge. UBD-evoked activity in Type II neurons was inhibited more than similar activity in Type I neurons by both intravenous morphine and lidocaine. These results support the assertion that at least two different populations of spinal dorsal horn neurons exist which encode for a stimulus of urinary bladder distension. These populations are an analogue to previously characterized, similar neuronal populations excited by colorectal distension and suggest that they are representative of the overall phenomenon of visceral sensory processing, a component of which is nociception.

Vigor of visceromotor responses to urinary bladder distension in rats increases with repeated trials and stimulus intensity.

This methodological study characterized visceromotor responses (VMRs) as abdominal contractile responses to urinary bladder distension (UBD) in the female rat. Electromyographic activity of the abdominal musculature was used as a measure of the VMR. Similar to previously characterized cardiovascular responses to UBD, VMRs to UBD demonstrated an initial sensitization period whereby repeated presentation of UBD stimuli led to increase vigor of the VMR. Graded UBD produced graded VMRs, therefore stimulus-response functions could be constructed. The intravenous administration of the opioid fentanyl produced a reduced vigor of the VMR in a fashion consistent with its analgesic effect. The present report supports the utility of this model for studies of urinary bladder nociception.

Chronic urologic pain syndromes.

Chronic pains typically evaluated by a urologist are discussed from the perspective of a non-urologist pain clinician. The pathophysiology of some pains is understood and so we believe the patient's symptoms: examples are cancer-related pain and recurrent urolithiasis. We treat these pains with traditional analgesics. Other pains, such as those of interstitial cystitis, chronic prostatodynia, and chronic orchialgia are less understood and so are treated in a more conservative and often empiric fashion. Proposed therapies for these disorders are discussed.

Inflammation enhances reflex and spinal neuron responses to noxious visceral stimulation in rats.

To improve understanding of sensory processes related to visceral inflammation, the effect of turpentine-induced inflammation on reflex (cardiovascular/visceromotor) and extracellularly recorded lumbosacral dorsal horn neuron responses to colorectal distension (CRD) was investigated. A 25% solution of turpentine, applied to the colorectal mucosa, produced inflammation, decreased compliance of the colonic wall, and enhanced reflex responses in unanesthetized rats within 2-6 h. At 24 h posttreatment, pressor responses to CRD (80 mmHg, 20 s) were 20% greater, and intraluminal pressures needed to evoke visceromotor reflexes were 30% lower than controls. Parallel electrophysiological experiments in spinal cord-transected, decerebrate rats demonstrated that two neuronal subgroups excited by CRD were differentially affected by turpentine administered 24 h before testing. During CRD, abrupt neurons were 70% less active and sustained neurons were 25% more active than similar neurons in controls. In summary, reflex and neuronal subgroup (sustained neurons) responses to CRD were both potentiated by chemical inflammation. This suggests that the neurophysiological basis for inflammation-induced increases in reflex responses to CRD is increased activity of this neuronal subgroup.

Characterization of pressor and visceromotor reflex responses to bladder distention in rats: sources of variability and effect of analgesics.

PURPOSE: We assessed the usefulness of cardiovascular and visceromotor responses to bladder distention as measures of acute visceral nociception in rats by determining the reliability of these responses. MATERIALS AND METHODS: Halothane anesthetized male and female Sprague-Dawley rats were acutely instrumented with tracheal, jugular venous, carotid arterial and bladder cannulas. Wires were inserted into the abdominal musculature to enable myoelectrical activity measurement. Anesthesia was decreased until flexion reflexes were present. Repeat phasic and graded bladder distention was administered, and arterial blood pressure and abdominal electromyography activity were continuously monitored. We determined the effects of gender, vaginal smear estrous cycle stage and drug treatment on the measured responses. RESULTS: Bladder distention produced reliable pressor and visceromotor (abdominal contractile) responses. There was great inter-animal variability in response vigor but good reproducibility was noted within individual animals. During slow bladder filling bladder contractions were not noted at this level of anesthesia. Sex differences included a more vigorous reflex response in females than in males, which was most vigorous in females in proestrus. Repeat bladder distention led to increasingly vigorous pressor responses and the improved reliability of visceromotor responses. Intravenous morphine and lidocaine dose dependently inhibited the reflex responses. CONCLUSIONS: Pressor and visceromotor responses to bladder distention in halothane anesthetized rats are reliable measures of acute bladder nociception that may prove useful for analgesic screening and in studies of hormonal effects on nociception.

Pharmacology of peripheral analgesia.

Pain may begin in the periphery with activation of nociceptor transducers. The present article reviews the pharmacology of drug action at the level of the primary afferent by discussing the following: [1] agents which block transduction processes (vanilloids, sodium ion channel blockers, antiserotonergic agents, antipurinergic agents); [2] agents inhibiting the transducer site (opioids, cannabinoids, alpha adrenergic agents); [3] agents blocking transducer-based modulation processes (anti-inflammatories, antikinin agents, antitachykinins); and [4] agents which block primary afferent-related modification processes (antineurotrophins). There is a clear role for many of these agents in the treatment of inflammatory pain and they have potential benefits for neuropathic pain with peripheral triggers.

Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord.

The effect of acute, mid-cervical spinal cord lesions on neuronal and reflex activity evoked by the noxious visceral stimulus, colorectal distension (CRD; 80 mmHg, 20 s), was determined in halothane-anesthetized rats. Extracellular recordings were performed of neurons stereotaxically located within the ventrobasal group of the thalamus and in the region of the medullary lateral reticular nucleus. CRD-evoked activity of thalamic neurons was attenuated by lesions of the dorsal midline, but minimally affected by lateral lesions of the spinal cord. In contrast, CRD-evoked activity of medullary neurons was attenuated by lateral lesions ipsilateral to the recording site, but minimally affected by contralateral lateral lesions or dorsal midline lesions. Pseudo-affective visceromotor/cardiovascular responses were vigorous in rats with dorsal midline lesions and absent/attenuated in rats with bilateral lateral spinal lesions. This study presents evidence that visceral nociceptive information ascends in the spinal cord by both dorsal midline and lateral spinal pathways.

Intravenous lidocaine inhibits visceral nociceptive reflexes and spinal neurons in the rat.

BACKGROUND: Systemically administered local anesthetics and other sodium channel blockers produce analgesia in patients with hypersensitivity disorders. To assess whether these agents have a role in the treatment of visceral pain, the present study examined the effects of intravenous lidocaine on neuronal and reflex responses to colorectal distension. METHODS: In decerebrate, cervical spinal cord-transected male rats, the lumbosacral spinal cord was exposed by a laminectomy. Dorsal horn neurons demonstrating excitatory responses to colorectal distension were identified using microelectrodes. Sequential doses of lidocaine were administered intravenously. In chronically instrumented, unanesthetized rats, visceromotor responses, pressor responses, and increases in heart rate were elicited by colorectal distension and sequential doses of lidocaine. RESULTS: Intravenous lidocaine dose-dependently inhibited visceromotor and cardiovascular reflexes and the evoked and spontaneous activity of neurons excited by colorectal distension. There were statistically greater effects on one of the neuronal subgroups (sustained neurons) than on another subgroup (abrupt neurons.) CONCLUSIONS: Intravenous lidocaine had dose-dependent, inhibitory effects on two spinal neuronal populations excited by colorectal distension and dose-dependently inhibited reflex responses to the same stimulus. This suggests there may be utility of sodium channel blockers in the treatment of pain of visceral origin.

Sex-related hormonal influences on pain and analgesic responses.

Considerable evidence indicates sex-related differences in pain responses and in the effectiveness of various analgesic agents. Specifically, females are at greater risk for experiencing many forms of clinical pain and are more sensitive to experimentally induced pain relative to males. Regarding analgesic responses, nonhuman animal studies indicate greater opioid analgesia for males, while a limited human literature suggests the opposite. Though the mechanisms underlying these effects remain unclear, the influence of gonadal hormones on nociceptive processing represents one plausible pathway whereby such sex differences could emerge. The present article reviews the complex literature concerning sex steroid effects on pain responses and analgesia. First, nonhuman animal research related to hormonal effects on nociceptive sensitivity and analgesic responses is presented. Next, human studies regarding gonadal hormonal influences on experimental pain responses are reviewed. Several potential mechanisms underlying hormonal effects on nociceptive processing are discussed, including hormonal effects to both peripheral and central nervous system pathways involved in pain transmission. Finally, based on these findings we draw several conclusions and make specific recommendations that will guide future research as it attempts to elucidate the magnitude and importance of sex-related hormonal effects on the experience of pain.

Low intensity vagal nerve stimulation lowers human thermal pain thresholds.

The effect of vagal nerve stimulation (VNS) on thermal pain sensation was studied in eight subjects who had vagal nerve stimulators surgically implanted for purposes of seizure control. Prior to their involvement in the study, all subjects had the intensity of their VNS (30 Hz, 0.5 ms, 1.0-2.75 mA) adjusted upwards until achieving their desired clinical effect of reduced seizures. Thermal pain thresholds were determined using a Medoc TSA-2001 with a thermode applied to the skin of the forearm. During VNS at settings 100% of those used clinically to control their seizures, subjects showed a statistically significant decrease in their thermal pain threshold of 1.1+/-0.4 degrees C. Acute effects of graded VNS on thermal pain thresholds were determined in seven of the subjects after cessation of chronic VNS. Two thermal threshold measurements were obtained while the subject received sham stimulation (0 mA intensity), during tactile control stimulation and during 30 s of VNS at intensities approximately 33, 66 and 100% of the settings utilized to control their seizures. Tactile control stimulation was provided by electrical stimulation of the skin of the ankle with the intensity adjusted by the patient to match the intensity of any sensations felt in the neck during VNS. Subjects were not aware of the settings employed. Their stimulator was adjusted with each trial and an ascending/descending ordering of intensity was utilized with an inter-trial interval of 2 min. Thermal pain thresholds were significantly decreased in relation to tactile control stimulation at all intensities of VNS tested with the greatest effect occurring at the 66% level. Subjects were also monitored non-invasively and hemodynamic responses to VNS were determined. No significant alterations in hemodynamic variables were observed. The findings of this human study are consistent with experiments in non-human animals which demonstrate a pro-nociceptive effect of low intensity VNS.

Acute inflammation differentially alters the activity of two classes of rat spinal visceral nociceptive neurons.

Quantitative neurophysiological studies have identified the presence of at least two spinal neuron populations (ABRUPT and SUSTAINED) which are excited by the noxious visceral stimulus colorectal distension (CRD). The present study examined the effects of acute colorectal inflammation on the activity of dorsal horn neurons in decerebrate, cervical spinal cord-transected male rats. Extracellular recordings were made using tungsten microelectrodes and inflammation was produced by intracolonic instillation of turpentine (25% solution). The total activity of SUSTAINED neurons during CRD increased starting one hour after turpentine instillation whereas the total activity of ABRUPT neurons during CRD, as a group, was unaffected during the two hours of study. Increases in total activity during CRD correlated with increases in spontaneous activity. These observations further support that visceral nociception travels by a dual pathway and suggest a predominant role for SUSTAINED neurons in the signaling of visceral pain-related events.