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Purpose: We quantified differences in somatic and visceral sensation in healthy subjects and subjects with interstitial cystitis (IC)., Materials and Methods: A total of 13 subjects with IC and 13 healthy subjects answered psychological questionnaires and underwent psychophysical testing of thermal and pressure thresholds for sensation as well as the ischemic forearm test of pain tolerance. A subset of subjects also underwent bladder sensory testing with the determination of 3 consecutive cystometrograms. Ratings of intensity and unpleasantness were determined., Results: Subjects with IC were significantly more sensitive to deep tissue measures of sensation related to pressure, ischemia and bladder than healthy subjects. Cutaneous thermal pain measures were similar in the 2 groups. Psychological measures indicated higher reactivity in subjects with IC., Conclusions: Similar to other visceral pain disorders, such as irritable bowel syndrome, hypersensitivity to somatic stimuli was noted in subjects with IC. This suggests altered central mechanisms in the processing of sensory events from the bladder.

Sex differences in pain perception and analgesic responses have garnered increasing attention in recent years. We examined the association of psychological factors to baseline pain perception and pentazocine analgesia among 49 healthy women and 39 men. Subjects completed psychological questionnaires measuring positive and negative affect as well as catastrophizing. Subsequently, responses to experimental pain were assessed before and after double-blind administration of intravenous pentazocine (0.5mg/kg). In correlational analyses, positive affect predicted lower pain sensitivity among men but not women. Negative affect predicted lower baseline pain tolerances among both sexes but predicted poorer analgesia only among men. Catastrophizing was associated with greater pain sensitivity and less analgesia more consistently in men than women. Regression models revealed that positive affect predicted lower overall pain sensitivity and catastrophizing predicted poorer overall analgesic responses among men, while no significant predictors of overall pain or analgesia emerged for women. Moreover, positive affect and catastrophizing were negatively and positively correlated, respectively, with side effects from the medication, but only among men. These findings indicate sex-dependent associations of psychological factors with baseline pain perception, analgesic responses, and medication side effects.

Responses to painful stimuli are characterized by tremendous interindividual variability, and genetic factors likely account for some proportion of this variability. However, few studies have identified genetic contributions to experimental pain perception in humans. This experiment investigated whether the A118G single nucleotide polymorphism of the mu-opioid receptor gene ( OPRM1 ) was associated with responses to three different experimental pain modalities in a sample of 167 healthy volunteers (96 female, 71 male). Responses to thermal, mechanical, and ischemic pain were assessed in all subjects, and genotyping of OPRM1 was performed, which revealed that the rare A118G allele occurred in 24 females (25%) and 12 males (17%). Statistical analyses indicated that subjects with a rare allele had significantly higher pressure pain thresholds than those homozygous for the common allele. Also, a sex by genotype interaction emerged for heat pain ratings at 49 degrees C, such that the rare allele was associated with lower pain ratings among men but higher pain ratings among women. These data indicate an association of a common single nucleotide polymorphism of OPRM1 with mechanical pain responses and that this genotype may be associated with heat pain perception in a sex-dependent manner. This study examines the association of the A118G SNP of OPRM1 to experimental pain sensitivity. The results indicate that the rare allele is associated with higher pressure pain thresholds. These results support previous contentions that OPRM1 may be a pain-relevant gene; however, replication of these findings is needed.

Unlabelled: Sex differences in analgesic responses to mu opioid agonists have been reported, although the direction of these differences varies across studies. To further characterize sex differences in responses to mu opioids, the analgesic effects of intravenous morphine (0.08 mg/kg) were determined in healthy women (n = 61) and men (n = 39) by using 3 experimental pain models, heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both morphine and saline, which occurred on separate days in counterbalanced order. Although morphine produced significant analgesic effects for all pain stimuli, no significant sex differences in morphine analgesia emerged. However, morphine attenuated cardiovascular reactivity to the ischemic pain task in men but not women, and women reported significantly more drug-related adverse effects than men. These findings are in contrast with some recent clinical and experimental results suggesting more robust analgesic response to mu opioids among women compared to men, although the data indicate that sex differences in non-analgesic effects of morphine were present. These results suggest that sex differences in responses to morphine might depend on the pain model and/or drug dose as well as the specific end point assessed., Perspective: This study examines morphine responses in women and men by using laboratory pain measures. The results indicate no sex differences in analgesia, but women reported greater side effects, and morphine attenuated cardiovascular responses more strongly among men than women. These results add to the literature regarding sex differences in response to opioids.

Background/objective: Few studies have examined the prevalence of visceral pain in persons with spinal cord injury (SCI), and virtually no studies have looked at the relationship between visceral pain and self-reported quality of life. We examined the frequency of reported visceral pain at 5, 10, and 15 years after injury to determine whether the presence of visceral pain is related to quality of life, and to determine to what extent visceral pain should be of concern to clinicians treating patients with SCI., Methods: Visceral pain and quality of life in persons with SCI were compared from a combined Craig Hospital and National Model SCI Systems database at 5 (N = 33), 10 (N = 132), and 15 (N = 96) years after injury., Results: The rates of visceral pain increased at each measurement (10% at year 5, 22% at year 10, and 32% at year 15); although these numbers reflect cross-sectional data, they do show a clear statistical change. Only a limited true longitudinal sample was available, but at 10 years after injury, individuals who had reported visceral pain at any time reported a significantly lower quality of life than those never experiencing visceral pain, F1,188 = 3.95, P < 0.05., Conclusions: Although visceral pain may not be as prevalent as the more researched neuropathic and musculoskeletal subtypes of pain, it may account for a higher percentage of people with SCI who report pain than previously recognized. More quantitative and longitudinal research is needed to examine the relationship of visceral pain with overall quality of life and to pursue interventions.

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.

A 2003 study suggested that there are age differences in diffuse noxious inhibitory controls (DNIC), a form of endogenous pain inhibition. The present report describes a followup study employing a pharmacological blockade of endogenous opioids, i.e., using naloxone, in a small subset (n=6) of healthy young volunteers to characterize the opioid-dependence of DNIC, as well as DNIC's association with cardiovascular reactivity. Findings suggested that, while opioid blockade enhanced cardiovascular reactivity to cold pain, DNIC was not affected by administering naloxone. Interestingly, greater cardiovascular responses to noxious cold were associated with enhanced DNIC in this small sample. This relationship, which did not appear opioid-dependent, supports previous models integrating cardiovascular activity with the functioning of pain-modulatory systems.

Background: Accumulating evidence suggests that there are sex differences in analgesic responses to opioid agonists. Several studies using an oral surgery pain model have reported more robust analgesia to kappa-agonist-antagonists (e.g., pentazocine, nalbuphine, butorphanol) among women than among men. However, evidence of sex differences in kappa-agonist-antagonist effects from studies of experimentally induced pain in humans is lacking., Methods: Therefore, the analgesic effects of intravenous pentazocine (0.5 mg/kg) were determined in healthy women (n = 41) and men (n = 38) using three experimental pain models: heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both pentazocine and saline, which occurred on separate days in counterbalanced order., Results: Compared with saline, pentazocine produced significant analgesic responses for all pain stimuli. However, no sex differences in pentazocine analgesia emerged. Effect sizes for the sex differences were computed; the magnitude of effects was small, and an equal number of measures showed greater analgesia in men than in women. Also, analgesic responses were not highly correlated across pain modalities, suggesting that different mechanisms may underlie analgesia for disparate types of pain., Conclusions: These findings indicate significant analgesic responses to pentazocine in both men and women across multiple experimental pain assays, and the absence of sex differences contrasts with previous data from the oral surgery model. The most likely explanation for the discrepancy in results is that of differences in the pain assays. These findings are important because they suggest that sex differences in opioid analgesia may be specific to certain types of pain.

Purpose: A mouse model of bladder distension (UBD) induced acute visceral nociception was characterized. Murine models of nociception may allow for the investigation of mechanisms of pain and analgesia through the use of genetic models., Materials and Methods: Isoflurane anesthetized, spontaneously breathing female C3H/J mice had 24 gauge intravesical catheters transurethrally placed and electrodes implanted in the abdominal musculature and in upper limbs for electromyograms and electrocardiograms., Results: UBD (10 to 80 mm Hg for 20 seconds, phasic air distention) produced reliable, reproducible visceromotor responses (VMRs), that is increased abdominal muscle activity, which were graded with graded UBD. Heart rate and respiratory responses were reliable but not reproducible. Subcutaneous morphine (1 to 4 mg/kg) and intravesical lidocaine (500 microg) produced reversible VMR inhibition. Inflammation produced by intravesical mustard oil (2.5% for 15 minutes with an olive oil control) produced a marked increase in sensitivity to UBD with more robust responses evoked by lower UBD intensities. VMRs were present in decerebrate but not in spinal cord transected mice. Unanesthetized mice had similar responses to UBD but with lower pressure thresholds for VMRs., Conclusions: These findings suggest the usefulness of the current model system for the study of bladder nociception. In mice UBD evoked VMRs are spinobulbospinal reflexes that are reliable and reproducible, graded in relation to the stimulus, inhibited by analgesics and augmented by the presence of inflammation. Together these data strongly support the use of this model because it may allow the assessment of pharmacogenetic differences among murine strains and the use of transgenic technologies.

Purpose: Fibreoptic intubation (FOI) has become an essential technique in the anesthetic management of patients with difficult airways. Unfortunately, residents may graduate from anesthesiology training programs with insufficient skills in FOI. To enhance resident proficiency at FOI without compromising patient comfort or safety, the technique of transnasal jet ventilation-assisted FOI was developed. This report describes our initial experience with this technique., Methods: Sixty-four patients scheduled for oromaxillofacial surgery under nasal endotracheal anesthesia were recruited. Twenty-eight residents at all levels of training performed FOI through the patient's right nostril after the induction of general anesthesia and neuromuscular blockade. Oxygenation and ventilation were maintained by a faculty anesthesiologist using a Sanders device to deliver a jet of oxygen through a nasal trumpet placed in the patient's left nostril. The time from induction until completion of the FOI was recorded. Residents were subsequently queried about the educational benefit of the technique using a standardized questionnaire., Results: All residents were able to successfully intubate all patients in this study. Thirteen residents successfully performed intubations on three or more occasions with 70% performing the technique faster on the third trial than on the first. No evidence of hypoxemia, gastric distension, pneumothorax, hemodynamic instability or recall was observed. All respondents to the questionnaire reported that the technique was useful as an educational tool and recommended its use with other residents., Conclusion: Transnasal jet ventilation-assisted FOI is a useful method to train residents in FOI while maximizing patient comfort and safety.

Laboratory pain research has been criticized as being irrelevant to the clinical experience of pain. Previous findings have been inconsistent with some studies suggesting that experimental pain responses may be related to the reported presence or severity of chronic pain, while others report no such associations. However, few of these studies assess a variety of laboratory pain responses, and none has assessed relationships between clinical pain and diffuse noxious inhibitory controls (DNIC) in healthy subjects. We administered questionnaire measures of pain, quality of life, and psychological variables to a sample of healthy adults participating in a laboratory study of age differences in pain responses. DNIC was not related to other laboratory pain responses, psychological variables, or physiological variables measured in the present study. Regression models predicting health-related quality of life (e.g. pain, physical functioning) revealed that age, sex, and DNIC responses explained between 10 and 25% of the variance in these dependent measures. Of the laboratory pain variables, only DNIC was the sole consistent predictor of clinical pain and physical health, with greater DNIC responses related to less pain, better physical functioning, and better self-rated health. In addition, age differences in DNIC appeared to partially mediate age differences in physical functioning. These findings highlight the potential clinical relevance of experimental pain procedures and suggest that DNIC may be the laboratory pain response most closely associated with clinical pain and health-related variables.

Background: Pain following spinal cord injury (SCI) has proved difficult to treat. Although the use of antiepileptic drugs to treat SCI-related pain has been studied previously, topiramate has not been investigated in this population. Our recent experience suggests that topiramate may be efficacious in the treatment of SCI-related pain., Method: Case Studies Findings: This report presents the clinical histories of two people with pain following SCI who reported beneficial effects of treatment with the new antiepileptic drug topiramate, even after failing treatment with standard analgesic medications. Topiramate was well tolerated in these patients., Conclusion: For post-SCI pain, topiramate appears to be an effective treatment in some patients. Based on the present anecdotal findings, larger controlled studies comparing topiramate with standard treatment for SCI-related pain are warranted.

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

Despite decades of research, hundreds of studies, and a number of recent reviews, the effects of aging on the experience of pain remain poorly understood. Many prior investigators have reported increases in persistent pain conditions and diminished tolerance for certain types of laboratory-induced pain among the elderly. While explanations for these effects often propose senescent decrements in endogenous analgesic systems as a possible contributory mechanism, almost no direct empirical evidence for this hypothesis has yet emerged in human studies. The present investigation was designed to evaluate the existence and nature of these putative age-related differences in endogenous pain inhibition. Groups of healthy younger (n=45, mean age=21.6 years, range=18-25) and older (n=48, mean age=63.1 years, range=55-67) adults participated in a controlled, two-session laboratory assessment of diffuse noxious inhibitory controls (DNIC), a measure of endogenous pain inhibition. In this study, we examined age differences in the effects of concurrent cold pain on ratings of heterotopically presented repetitive noxious thermal stimuli. Interestingly, older adults demonstrated facilitation rather than inhibition of thermal pain during concurrent noxious cold stimulation while younger adults demonstrated some expected DNIC effects (i.e. a reduction in thermal pain ratings during heterotopic stimulation with noxious cold). Collectively, the findings of the present study suggest age-associated decrements in at least one form of endogenous analgesic response. If replicated, such findings of reduced pain-modulatory capacity in the elderly may partially explain age-related differences in the prevalence, severity, and impact of chronic pain.

Peripheral analgesia produced by the intravesical instillation of dimethyl sulphoxide (DMSO) and capsaicin has been used to treat visceral pain originating in the urinary bladder. The present study sought to determine the neurophysiologic consequences of the intravesical instillation of these compounds by measuring spinal neuronal responses evoked by urinary bladder distension (UBD) in the rat. Subjects were spinally transected, decerebrate female Sprague-Dawley rats. The effect of 0.5 mL of solution of 10% or 50% DMSO, 100 micromol/L capsaicin, or the same volume of saline instilled into the bladder on excitatory neuronal responses to UBD was studied by using single-unit extracellular recordings of L6-S2 dorsal horn spinal cord neurons. Fifty-six dorsal horn neurons that were excited by UBD in a graded fashion were identified. All neurons were also excited by noxious or non-noxious cutaneous stimuli. Two hours after intravesical instillation, solutions of 50% DMSO or 100 micromol/L of capsaicin produced a reduction of the slope of stimulus-response functions for neuronal activity evoked by graded UBD. These data support a local effect of intravesical 50% DMSO or capsaicin and suggest the use of this model to study novel peripheral treatment strategies for bladder pain.

Background: Ketamine is analgesic in experimental and clinical studies of inflammatory, neuropathic, and postoperative pain. Its role in the treatment of visceral pain is less known. The authors investigated the effect and site of action of ketamine on reflex responses evoked by urinary bladder distension (UBD). The effects of other clinically available N-methyl-d-aspartate (NMDA) receptor antagonists on these responses were also studied., Methods: The effect of intravenous ketamine (1, 3, and 10 mg/kg), dextromethorphan (5 mg/kg), and memantine (16 mg/kg) on mean arterial pressure changes (Delta MAP) and abdominal electromyographic activity (EMG) evoked by UBD was measured in anesthetized rats. Ketamine was also administered intravesically and intrathecally and its effect on Delta MAP and EMG responses to UBD recorded. The effect of pretreatment with intravenous ketamine on these responses was also assessed., Results: The Delta MAP and EMG responses to UBD were reduced in a dose-dependent fashion by ketamine. Memantine and dextromethorphan also inhibited these responses. Ketamine administered intrathecally produced marked inhibition of Delta MAP and EMG responses to UBD. Pretreatment with ketamine only transiently reduced the vigor of responses to UBD., Conclusions: Ketamine inhibited, in a dose-dependent fashion, the Delta MAP and EMG responses to UBD, an effect likely caused by actions within the spinal cord. Similar inhibition observed with systemic dextromethorphan and memantine treatments suggests that the analgesic effect of ketamine is caused by antagonism of the NMDA receptor. Pretreatment with ketamine did not have a preventive effect in this model of bladder nociception.

Background: The effect of ketamine as a treatment of visceral pain is not known. The current study investigated the effect of ketamine on spinal dorsal horn neurons excited by urinary bladder distension (UBD). The effect of other clinically available N-methyl-D-aspartate receptor antagonists on these responses was also studied., Methods: Extracellular recordings of neurons located in the L6-S2 spinal dorsal horn of cervical spinal cord-transected, decerebrate female rats were obtained. Cutaneous receptive fields of neuronal units excited by UBD were characterized for responses to segmental noxious and nonnoxious stimuli. Nonsegmental noxious stimuli were also applied, and neurons were classified as type I (inhibited) and type II (noninhibited) by the stimulus. The effect of intravenous ketamine (1, 3, and 10 mg/kg), dextromethorphan (5 mg/kg), and memantine (16 mg/kg) on neuronal responses of these units was measured., Results: Spontaneous and evoked neuronal activity to UBD was reduced in a dose-dependent fashion by ketamine. Responses to nonnoxious cutaneous stimuli were also significantly reduced after treatment. Dextromethorphan inhibited neuronal activity evoked by UBD in type I neurons. A similar selective effect of treatment on type I versus type II neurons was observed after intravenous ketamine and memantine., Conclusions: Intravenous ketamine produces dose-dependent inhibition of the spinal cord neuronal responses evoked by UBD. All three N-methyl-D-aspartate receptor antagonists showed selective effects on spinal cord neurons subject to counterirritation. This neurophysiologic evidence supports a spinally mediated analgesic effect of ketamine in this model of urinary bladder nociception, an effect likely caused by N-methyl-D-aspartate receptor antagonism.

Topically applied single or multiagent analgesics compounded by specialty pharmacies are utilized by an unknown number of pain clinicians to unknown effect. To assess the use and perceived efficacy of these agents, an e-mail survey of members of the American Society of Regional Anesthesia and Pain Medicine was performed. Response rate was low, but identified use of compounded topical agents throughout the United States. Of the 120 clinicians responding, 27% (n = 32) reported that they prescribed compounded topical analgesics containing 1 to 5 agents (mean + SEM; 2.6 +/- 0.2) in their practice 3.5 +/- 0.6 times per month. Use of 36 different agents of varying concentrations was reported. These clinicians perceived that 43% +/- 4% of treated patients responded favorably to the topical agents with an average of 47% +/- 3% pain relief and few side effects. Despite favorable reports of benefit, most clinicians perceived use of such compounded agents in their regions to generally be "little or none."

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.

Background and Objectives: Interscalene brachial plexus block is often used for surgeries involving the shoulder and upper arm. Known complications include phrenic nerve paralysis, intravascular injection, and cervical epidural block. We report a patient who developed acute hypoxia immediately following this block, presumably secondary to an acute pulmonary thromboembolus (PTE) coupled with phrenic nerve paralysis., Case Report: A 43-year-old man with end-stage renal disease secondary to hypertension was scheduled for primary placement of a left upper extremity arteriovenous fistula. A technically unremarkable interscalene brachial plexus block was performed using a 22-gauge regional block needle and 35 mL of 1.5% mepivacaine. Immediately following injection, the patient's oxygen saturation decreased from 99% to 85%, and he complained of chest pain and shortness of breath and developed hemoptysis. Workup revealed an elevated hemidiaphragm, but no pneumothorax or evidence of local trauma. A spiral computed tomogram (CT) suggested acute pulmonary thromboemboli as the etiology of the hypoxia and hemoptysis, although the diagnosis was uncertain., Conclusions: This case report suggests that manipulations and vasodilation related to an interscalene block may have facilitated the dislodgement of a pre-existing upper extremity thrombus.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Unlabelled: A population of neurons resident in the caudal ventrolateral medulla are excited by noxious cutaneous and visceral stimuli from large portions of the body. These neurons act as monitors of ascending nociceptive information, and we hypothesized that they would be inhibited by spinally administered analgesics in a clinically relevant fashion. Rats were anesthetized with oxygen/ halothane. The caudal medulla was surgically exposed, and a catheter placed into the intrathecal space overlying the lower thoracic spinal cord via the surgical site. Single medullary neurons were characterized for responses to cutaneous and visceral (colorectal distension) stimuli. The effects of i.v. and intrathecally administered morphine and lidocaine were determined. The intrathecal infusion of morphine for 6 days before testing was also used as a pretreatment. Colorectal distension-evoked responses of medullary nociceptive neurons were inhibited in a dose-dependent, naloxonereversible fashion by intrathecal and i.v. morphine (50% effective dose values: 3.5 and 440 microg/kg, respectively). Intrathecal lidocaine abolished responses to colorectal distension and produced a spinal level at doses producing minimal effects when administered systemically. Prior treatment with an infusion of morphine produced tolerance to the effects of subsequent intrathecal morphine administration. These findings support the use of this preparation as a neurophysiologic model of spinal analgesia., Implications: Neurons in the brainstem, isolated electrophysiologically, were used as whole body monitors of pain-related activity in the rat. As a neurophysiologic model of nociception, this preparation may prove useful for the study of regionally administered analgesics and local anesthetics.

Background & Aims: Quantitative neurophysiological studies have identified the presence of at least 2 spinal neuronal populations (abrupt and sustained) that are excited by the noxious visceral stimulus colorectal distention. This study examined the effects of the kappa opioid receptor agonists fedotozine and U50488H on the activity of these neurons., Methods: In decerebrate, cervical spinal cord-transected male rats, the lumbosacral spinal cord was exposed by a laminectomy. Dorsal horn neurons showing excitatory responses to colorectal distention (80 mm Hg, 20 seconds) were identified using microelectrodes. Cumulative doses of fedotozine and U50488H were administered intravenously or intrathecally, and antagonists were used., Results: Intravenous fedotozine and U50488H dose-dependently inhibited the evoked activity of sustained neurons. This inhibition was partially reversed by the kappa opioid antagonist norbinaltorphimine. The same agents had insignificant effects on the evoked activity of abrupt neurons. Fedotozine inhibited spontaneous activity of both abrupt and sustained neurons. Intrathecally administered U50488H had no effect on abrupt or sustained neurons, but intrathecally administered fedotozine inhibited the evoked and spontaneous activity of both groups., Conclusions: Kappa opioid receptor agonists acting peripherally had differential effects on 2 spinal neuronal populations responsive to colorectal distention. Fedotozine had additional inhibitory effects acting within the spinal cord.

Pains arising from the viscera constitute a large portion of clinically treated pains. They are characterized by poor localization; immobility with tonic increases in muscle tone; and vigorous but nonspecific changes in autonomic function, such as changes in respiration, heart rate, and blood pressure. Tissue-damaging stimuli do not reliably produce visceral pain, so the study of visceral nociception in nonhuman animals requires identification of appropriate stimuli and responses. This article defines "noxious" visceral stimuli as those that produce pain in humans, result in aversive behaviors in animals, and evoke responses that are inhibited by manipulations known to be analgesic in humans. To be valid, the measured responses must be reliable, inhibited by known analgesics, and not inhibited by nonanalgesics. Using these criteria as measures of validity, the author examined several visceral pain models. The writhing test (application of intraperitoneal irritants) failed to meet these criteria; however, responses to small bowel distension, colonic-rectal distension, artificial ureteral calculosis, urinary tract distension, and the intravesical application of irritants met most, if not all, of the criteria. Other models, such as responses to biliary system distension, to reproductive organ stimulation, to the focal application of algesic agents onto various viscera, and to ischemic stimuli, met some of these criteria. This information should assist readers in decisions related to the use of visceral pain models.

In 71 halothane-anesthetized rats, we characterized the responses of single neurons in the nucleus ventroposterolateralis (VPL) of the thalamus to a noxious visceral stimulus (colorectal balloon distension; CRD) and studied the effects of intravenous morphine on these responses using standard extracellular microelectrode recording techniques. One hundred nine neurons were isolated on the basis of spontaneous activity. Sixty-four (59%) responded to CRD, of which 52 (81 %) had excitatory and 12 (19%) had inhibitory responses. Neurons showed graded responses to graded CRD pressures (20-100 mmHg), with maximum excitation or inhibition occurring at 80 mmHg. Responses to noxious (pinch, heat) and innocuous (brush, tap) cutaneous stimuli were studied in 95 of the VPL neurons isolated. Eighty-three of these neurons (48 CRD responsive and 35 CRD nonresponsive) (87%) had cutaneous receptive fields, of which 96% were small and contralateral and 4% were large and contralateral or bilateral. Ninety-four percent of these neurons responded to both noxious and innocuous cutaneous stimulation, and 6% responded to only noxious stimulation. No neurons responded solely to innocuous stimulation. Cumulative doses of morphine (0.125, 0.25, 0.5, 1, and 2 mg/kg, i.v) produced statistically significant dose-dependent attenuation of neuronal responses to CRD. Naloxone (0.4 mg/ kg, i.v.) reversed the effects of morphine. Morphine and naloxone had no significant effects on spontaneous activity. These data support the involvement of VPL neurons in visceral nociception and are consistent with a role of VPL in sensory-discriminative aspects of nociception.

This article has described the physiologic impact of trauma- and burn-related pain as well as the effect of a clinician's choice of analgesic method, using the specific example of regional analgesia for pain caused by chest trauma. It has been observed that trauma exerts a holistic influence upon the organism, marshalling reflexes, multi-system physiologic stress responses, and psychologic responses--some adaptive and others maladaptive. There is reason to consider that timely analgesia can intervene in this dynamic process and interdict the establishment of a debilitated state. A key finding of these studies is that a report of pain relief may not be the best outcome measure since the choice of analgesic method(s) has a significant impact on the secondary effects of pain. Although extrapolated from studies of perioperative pain, findings do suggest that there may be a critical period of time during which the secondary effects of a painful stimulus may be attenuated or reversed. How long this period of reversibility exists has not been determined, so planning for the level and goals of analgesia intervention should occur early on. Analgesia should be viewed not only as a humanitarian gesture, but also a therapeutic maneuver with the goal being the early restoration of function and the mitigation of a chronic debilitated state. There is scattered evidence that regional analgesic techniques using local anesthetics have some advantages over other analgesic modalities, particularly in the trauma patient with pulmonary compromise; however, as with other medical interventions, one should develop a strategic plan of application which includes consideration of potential complications and side effects, in addition to the potential therapeutic effects. The traumatized body, as well as the attending physician, must deal with inflammation, the neurohumoral reaction, musculoskeletal reflex responses, and numerous other reactions designed to stabilize an acutely destabilized systemic entity. Multimodal analgesia, with the balanced use of systemic and regional medications, has given the best short- and long-term results in studies of postthoracotomy pain. The use of a similar combined plan for posttraumatic analgesia seems logical; however, many questions remain as yet unanswered. In particular, what are the optimal combinations of techniques/medications to employ to maximize analgesia and minimize secondary effects of trauma? Can an aggressive multimodal approach intervene effectively in the development of chronic pain states, and if so, for how long? What are the long-term benefits to be derived from making a significant impact on the stress response? Last, but not least, can analgesic interventions be shown to be cost-effective according to current societal pressures to reduce the cost of health care? These and other questions are not easy to answer. Trauma strikes, in a variable fashion, patients of all ages, with all forms of comorbidity, and is treated by a technology that continues to evolve. Previous research related to the effects of analgesic treatments has been hampered by the limitations that arise when isolated groups embark on vast projects with limited numbers of patients available. It is time for investigators at multiple centers to embark on coordinated efforts to address long-term questions related to trauma and the therapeutic efficacy of analgesia.

Central pain following spinal cord injury is poorly understood, and is often resistant to conventional pain therapy regimens. We describe an individual with paraplegia who for many years experienced rapidly fluctuating, severe, unilateral pain below the level of his lesion. Prior to the initiation of pharmacological treatment, regional cerebral blood flow (rCBF) was measured during PAIN and NON-PAIN states using single photon emission computed tomography (SPECT). When experiencing pain, the subject had increased anterior cingulate gyrus blood flow, increased thalamic blood flow bilaterally and increased somatosensory cortex blood flow contralaterally but decreased caudate blood flow bilaterally. The subject's subsequent clinical course included a trial of gabapentin which produced a substantial reduction in frequency and average intensity of his episodic pain and which has been maintained for almost 2 years. This case demonstrates the correspondence between rCBF and pain associated with spinal cord injury and also suggests the potential utility of gabapentin for treatment of this central pain state.

In halothane-anesthetized rats, 283 caudal medullary neurons responsive to colorectal distension (CRD) were characterized using extracellular electrodes. Neurons inhibited by CRD (n = 82) were in the area dorsal to the lateral reticular nucleus (LRN). Most neurons excited by CRD (n = 130) were located within or immediately adjacent to the LRN, were excited by noxious heat and/or noxious pinch of at least half the body surface and were called bilateral nociceptive specific (bNS) neurons. bNS neurons had accelerating responses to graded CRD (threshold: 20 +/- 2 mmHg). Ten of twelve bNS neurons tested could be antidromically activated by electrical stimulation of the midline cerebellum. Other neurons excited by CRD (n = 71) had mixed responses to cutaneous stimuli and were generally located in the area dorsal to the LRN. Increases in blood pressure due to intravenous phenylephrine did not significantly alter the spontaneous activity of neurons excited by CRD, but altered spontaneous activity (12 excited, four inhibited) in all neurons tested which were inhibited by CRD. Decreases in blood pressure produced by intravenous nitroprusside produced a reciprocal response in most neurons inhibited by CRD and had a delayed onset (20-30 s after bolus administration) excitatory effect on 21 of 27 units excited by CRD. Combined with other studies, these data suggest a role for neurons within and adjacent to the LRN in the modulation of visceral nociception. They also implicate a role for the cerebellum in visceral nociceptive processing.

The development of tolerance to intrathecal morphine was studied in rats chronically implanted with intrathecal catheters connected to osmotic minipumps. Measures of cutaneous nociception were the hot plate (HP) and tail flick (TF) tests. Measures of visceral nociception were visceromotor (VM) responses to ramped colorectal distension (CRD) and cardiovascular (CV) responses to phasic colorectal distension. Tolerance to a continuous infusion of 6 or 20 nmol/h of morphine sulfate developed over 6 days. A significant reduction in the dose-dependent effects of intrathecal morphine in the TF and HP tests and VM and CV responses to CRD occurred in rats receiving continuous infusions of morphine. The development of tolerance to intrathecal morphine was similar in both cutaneous and visceral models.

Psychophysical studies were performed in 10 healthy, female volunteers using urinary bladder distension (UBD) as a visceral stimulus. Stimulus methodology was similar to that used clinically for obtaining cystometrograms with a fixed-rate (100 cc/min normal saline) filling of the urinary bladder, occasional pauses and simultaneous measure of bladder pressure using a catheter-transducer assembly. During bladder filling, subjects were asked to report sensations by verbal report and by using an electronic, hand-held, visual-analog-scale device. Sensations evoked by UBD were generally localized to the suprapubic region. UBD produced cardiovascular responses which increased with repeated trials. Sensation intensity increased with repeated UBDs as indicated by global pain ratings. Intravesical pressure and volume correlated with sensation intensity. The volume of distending fluid needed to produce a report of discomfort was highly variable from trial to trial and did not change significantly with repeated UBDs. The intravesical pressure which produced a report of discomfort was less variable and significantly decreased with repeated UBDs. The change in intravesical pressure and volume needed to produce discomfort was inversely correlated with initial intravesical pressure measures. Similar to findings in other organ systems, these findings demonstrate that repeated presentations of a visceral stimulus may lead to an increase in physiological and perceptual responses to pain.

In halothane-anesthetized rats, we characterized the responses of single neurons in the nuclei of medial thalamus (MT), specifically the mediodorsal thalamic nucleus (MD) and the nucleus submedius (Sm), to a noxious visceral stimulus (colorectal balloon distension, CRD), and studied the effects of intravenous morphine (Mor) on these responses using standard extracellular microelectrode recording techniques. 62 MD and 46 Sm neurons were isolated on the basis of spontaneous activity. 47 of the MD neurons (76%) responded to CRD, of which 70% had excitatory and 30% had inhibitory responses. 38 of the Sm neurons (83%) responded to CRD, of which 89% had excitatory and 11% had inhibitory responses. Responses of MD and Sm neurons excited by CRD were related significantly to distension pressure (20-100 mmHg), with maximum excitation occurring at 60 and 100 mmHg, respectively. MD neurons inhibited by CRD also had graded responses to graded CRD, with maximum inhibition occurring at 80 mmHg. The responses to noxious (pinch, heat) and nonnoxious (tap, brush) cutaneous stimuli were studied in 59 of the MD and 44 of the Sm neurons isolated. 22 of the MD neurons (37%) studied had cutaneous receptive fields, of which 59% were large and bilateral, 41% were small and usually contralateral receptive fields. 55% of these neurons were nociceptive-specific, 45% responded to both noxious and nonnoxious cutaneous stimulation. 29 of the Sm neurons (66%) studied had cutaneous receptive fields, of which 72% were large and usually bilateral, 14% were small and bilateral, 14% were small and contralateral receptive fields. 90% of these neurons were nociceptive-specific, 10% responded to both noxious and nonnoxious stimulation. No MD or Sm neurons responded exclusively to nonnoxious cutaneous stimulation. Mor (0.125, 0.25, 0.5 and 1 mg/kg I.V.) attenuated MD and Sm neuronal excitatory responses to CRD in a dose-dependent fashion, abolishing evoked activity with a dose of 0.5 mg/kg (p < 0.05) and 1 mg/kg (p < 0.05), respectively. Naloxone (0.4 mg/kg I.V.) reversed the effects of Mor. Mor and naloxone had no effects on spontaneous activity. These data support the involvement of MD and Sm neurons in visceral nociception, and are consistent with a role of Sm in affective-motivational, and MD in both sensory-discriminative and affective-motivational aspects of nociception.

'Noxious' stimuli are pain-producing stimuli and have been traditionally defined as tissue damaging. This definition is not valid for visceral stimuli. Hence, behavioral definitions are needed. Awake, unanesthetized rats learned to passively avoid colorectal distension. The rate of acquisition increased as a function of the distending pressure. Two manipulations, intrathecal morphine and neonatal treatment with capsaicin, attenuated acquisition of avoidance behavior whereas the production of colorectal inflammation using turpentine enhanced acquisition of this behavior. These findings are consistent with the hypothesis that aversion to the stimulus is due to the 'noxious' nature of the stimulus.

1. Numerous studies have demonstrated that neural, behavioral, and reflex responses to a nociceptive test stimulus are inhibited by conditioning nociceptive stimuli; this inhibition has supraspinal, intraspinal, and segmental components. The general phenomenon is defined here as nocigenic inhibition. The present study of nocigenic inhibition documents that noxious cutaneous pinch and heat, used as conditioning stimuli, inhibit neuronal and reflex responses evoked by a noxious visceral stimulus, colorectal distension. 2. A total of 196 dorsal horn neurons were examined: 110 were short latency-abrupt (SL-A) neurons that were excited at short latency by colorectal distension and returned to baseline activity abruptly after termination of the distending stimulus, and 86 were short latency-sustained (SL-S) neurons that also were excited by colorectal distension at short latency, but demonstrated after-discharges for 4-240 s after termination of the distending stimulus. All SL-A and SL-S neurons studied had convergent cutaneous receptive fields. 3. The spontaneous activities of 100% of the 110 SL-A neurons tested were inhibited by greater than 25% by noxious pinch in sites distant from their convergent cutaneous receptive fields. In both anesthetized, intact, and spinalized rats, noxious conditioning pinch or noxious conditioning heat significantly reduced responses of SL-A neurons during noxious test colorectal distension. The magnitude of this nocigenic inhibition was graded with the intensity of the noxious conditioning stimulus. Noxious conditioning tail heating produced a parallel shift to the right in stimulus-response functions relating neuronal responses to the intensity of colorectal distension (20-100 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Nocigenic inhibition is the inhibition of neural, behavioral, or reflex responses to a nociceptive test stimulus produced by another, conditioning, nociceptive stimulus. The present study examines whether a natural noxious visceral stimulus, colorectal distension, used as a conditioning stimulus would inhibit neuronal or reflex responses to noxious cutaneous stimuli. Segmental effects of colorectal distension have been previously characterized; hence conditioning effects of colorectal distension on stimuli applied at sites distant (heterosegmental effects) and adjacent (perisegmental effects) to those areas of the spinal cord that receive the greatest afferent input from the colon were examined. The conditioning effects of colorectal distension were compared with those of noxious pinch. 2. Heterosegmental effects of colorectal distension were studied in 129 neurons located in the area of the trigeminal nucleus caudalis and cervical spinal dorsal horn. Steady-state activity (spontaneous activity or activity evoked by sustained pressure) of 106 of 129 trigeminal-cervical dorsal horn neurons was inhibited by both noxious colorectal distension (100 mmHg, 20 s) and noxious pinch of the tail; all neurons inhibited by colorectal distension were also inhibited by noxious pinch. Inhibition was graded with the intensity of the distending stimulus. The class 2-class 3 classification system (neurons excited by nonnoxious and noxious or only by noxious cutaneous stimuli, respectively) was roughly predictive of susceptibility to nocigenic inhibition, because 74 of 75 class 2 neurons tested were inhibited by noxious colorectal distension or noxious pinch and only 32 of 54 class 3 neurons were similarly inhibited. Five neurons were excited by colorectal distension, all of which were class 3 neurons. 3. Perisegmental effects of colorectal distension were observed in 100 L3-L5 spinal dorsal horn neurons. The spontaneous activities and responses during noxious test heating of the glabrous skin of the hindpaw of these neurons were affected in the same way by noxious (conditioning) colorectal distension. All neurons inhibited by colorectal distension (51 class 2 and 8 class 3 neurons) were also inhibited by noxious pinch of the nose or forepaw. The magnitude of the nocigenic inhibition of responses during heating of the hindpaw was graded with the intensity and duration of the noxious conditioning colorectal distension, was a function of the number of preceding distensions given to the rat, and outlasted the distending stimulus. Conditioning colorectal distension also produced a parallel shift to the right in stimulus-response functions relating responses of neurons to the intensity of the noxious test stimulus (42-50 degrees C).(ABSTRACT TRUNCATED AT 400 WORDS)

Deep pain arising from muscle, joints, connective tissue, and the viscera is different in character and quality from pain arising from cutaneous structures. Deep pains, particularly visceral pain, are poorly localized, typically referred or transferred to a cutaneous site, and generally produce strong emotional and autonomic responses and tonic muscle contractions. Despite the prevalence and clinical importance of deep pains, it is only relatively recently that investigative efforts have begun to focus on the mechanisms of deep pain. The present report briefly reviews the development and use of a model of visceral pain that employs constant pressure distension of the colon and rectum as a noxious stimulus. Converging behavioral, pharmacological, and physiological evidence that colorectal distension is a valid, reliable, noxious, visceral stimulus is presented.