Timothy J. Ness

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

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 κ-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 κ-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 κ-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the κ-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.

Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults

&NA; 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.

Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables.

&NA; 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.

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.

A preliminary study of the optimal anesthesia positioning for the morbidly obese patient.

Background: Hypoxemia during the induction of general anesthesia for the morbidly obese patient is a major concern of anesthesiologists. The etiology of this pathophysiological problem is multifactorial, and patient positioning may be a contributing factor. The present study was designed to identify optimal patient positioning for the induction of general anesthesia that minimizes the risk of hypoxemia in these patients. Methods: 26 morbidly obese patients (body mass index - BMI 56±3) were randomly assigned to one of three positions for induction of anesthesia: 1) 30° Reverse Trendelenburg; 2) Supine-Horizontal; 3) 30° Back Up Fowler. Mask ventilation, full neuromuscular paralysis and direct laryngoscopy were performed. Any airway difficulties were noted. After endotracheal tube placement, subjects were ventilated for 5 minutes with 1% isoflurane in a mixture of 50% oxygen / 50% air and then disconnected from the ventilation circuit.The time required for capillary oxygen saturation (SaO2), as measured by pulse oximeter, to decline from 100% to 92% was noted and identified as the safe apnea period (SAP). Ventilation was then immediately re-established.The lowest SaO2 after resuming ventilation and the time from that nadir to an SaO2 of 97% were also recorded. Results: BMI and hip-waist ratios of patients in groups 1, 2 and 3 did not significantly differ. There were no differences in airway difficulties between the different groups. The SAP in groups 1, 2 and 3 was 178±55, 123±24 and 153±63 seconds, respectively. The SaO2 of patients in the reverse Trendelenburg position dropped the least and took the shortest time to recover to 97%. Conclusions: In morbidly obese patients, the 30° Reverse Trendelenburg position provided the longest SAP when compared to the 30° Back Up Fowler and Horizontal-Supine positions. Since on induction of general anesthesia morbidly obese patients may be difficult to mask ventilate and/or intubate, this extra time may preclude adverse sequelae resulting from hypoxemia. Therefore, Reverse Trendelenburg is recommended as the optimal position for induction.

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

&NA; 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. Pseudaffective 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.

Sex-related psychological predictors of baseline pain perception and analgesic responses to pentazocine

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.

Low intensity vagal nerve stimulation lowers human thermal pain thresholds

&NA; 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°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.

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.

Experimental pain models reveal no sex differences in pentazocine analgesia in humans.

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 κ-agonist–antagonists (e.g., pentazocine, nalbuphine, butorphanol) among women than among men. However, evidence of sex differences in κ-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.