Janean E. Holden

The endogenous opioid system and clinical pain management.

The endogenous opioid system is one of the most studied innate pain-relieving systems. This system consists of widely scattered neurons that produce three opioids: beta-endorphin, the met- and leu-enkephalins, and the dynorphins. These opioids act as neurotransmitters and neuromodulators at three major classes of receptors, termed mu, delta, and kappa, and produce analgesia. Like their endogenous counterparts, the opioid drugs, or opiates, act at these same receptors to produce both analgesia and undesirable side effects. This article examines some of the recent findings about the opioid system, including interactions with other neurotransmitters, the location and existence of receptor subtypes, and how this information drives the search for better analgesics. We also consider how an understanding of the opioid system affects clinical responses to opiate administration and what the future may hold for improved pain relief. The goal of this article is to assist clinicians to develop pharmacological interventions that better meet their patients analgesic needs.

Enkephalin neurons that project to the A7 catecholamine cell group are located in nuclei that modulate nociception: ventromedial medulla

The location of methionine enkephalin neurons in the medulla oblongata that project to the dorsolateral pontine tegmentum was investigated using anterograde and retrograde tract tracing combined with immunocytochemical neurotransmitter identification. The results of these experiments demonstrate that enkephalinergic neurons from areas known to modulate nociception project to the region of the A7 catecholamine cell group in the dorsolateral pontine tegmentum. The medullary nuclei that contain these enkephalinergic neurons include the nucleus raphe magnus and the nucleus reticularis gigantocellularis pars alpha in the ventromedial medulla. While some of these enkephalinergic axons appose the somata and dendrites of A7 neurons, the majority of these axons appear to contact non-catecholamine neurons in the dorsolateral pontine tegmentum. Unidentified neurons located in the nucleus raphe magnus, the nucleus reticularis gigantocellularis pars alpha, and the nucleus reticularis gigantocellularis also project to the A7 area. Many of the neurons in the nucleus reticularis gigantocellularis pars alpha appear to contact both noradrenergic A7 neurons and non-catecholamine neurons in the dorsolateral pontine tegmentum, whereas most of those in the nucleus raphe magnus appear to contact non-catecholamine neurons. The anatomical findings described in this report and the results of preliminary behavioral studies provide evidence to support a model in which activation of the enkephalin-containing neurons in the ventromedial medulla facilitates nociception, while the non-enkephalin neurons mediate part of the antinociception produced by stimulating sites in the ventromedial medulla.

Repressive coping style: Relationships with depression, pain, and pain coping strategies in lung cancer out patients

Researchers have shown that coping style is related to pain and adjustment in people with chronic illness. This study was the first to examine how coping style related to pain, pain coping strategies, and depression in lung cancer outpatients. We conducted a comparative, secondary data analysis of 107 lung cancer patients (73% male, mean age 61.4±10.43 years, 88% Caucasian). As in prior studies, we classified patients into four coping style groups based on Marlowe-Crowne Social Desirability Scale and trait anxiety scores. The coping style groups were low-anxious (n=25); high-anxious (n=31); defensive high-anxious (n=21); and repressive (n=30). Compared to other coping style groups, the repressive group reported statistically significant lower mean scores for pain quality, pain catastrophizing, and depression. Assessing coping style by measuring personal characteristics such as social desirability and trait anxiety may help clinicians to identify vulnerable individuals with lung cancer who may be candidates for early and timely intervention efforts to enhance adjustment to pain.

Stimulation of the lateral hypothalamus produces antinociception mediated by 5-HT1A, 5-HT1B and 5-HT3 receptors in the rat spinal cord dorsal horn

The lateral hypothalamus is part of an efferent system that modifies pain at the spinal cord dorsal horn, but the mechanisms by which lateral hypothalamus-induced antinociception occur are not fully understood. Previous work has shown that antinociception produced from electrical stimulation of the lateral hypothalamus is mediated in part by spinally projecting 5-hydroxytryptamine (5-HT) neurons in the ventromedial medulla. To further examine the role of the lateral hypothalamus in antinociception, the cholinergic agonist carbamylcholine chloride (125 nmol) was microinjected into the lateral hypothalamus of female Sprague-Dawley rats and nociceptive responses measured on the tail-flick and foot-withdrawal tests. Intrathecal injections of the selective 5-HT1A, 5-HT1B, 5-HT3 receptor antagonists, WAY 100135, SB-224289, and tropisetron, respectively, and the non-specific antagonist methysergide, were given. Lateral hypothalamus stimulation with carbamylcholine chloride produced significant antinociception that was blocked by WAY 100135, tropisetron, and SB-224289 on both the tail-flick and foot-withdrawal tests. Methysergide was not different from controls on the tail flick test, but increased foot-withdrawal latencies compared with controls. These results suggest that the lateral hypothalamus modifies nociception in part by activating spinally projecting serotonin neurons that act at 5-HT1A, 5-HT1B, and 5-HT3 receptors in the dorsal horn.

Antinociception from lateral hypothalamic stimulation may be mediated by NK1 receptors in the A7 catecholamine cell group in rat

Stimulation of the lateral hypothalamus (LH) produces antinociception that is modified by intrathecal alpha-adrenergic antagonists. Spinally-projecting noradrenergic neurons in the LH have not been identified, suggesting that the LH may innervate brainstem noradrenergic neurons, such as the A7 catecholamine cell group in the dorsolateral pontine tegmentum, that modify nociception at the level of the spinal cord dorsal horn. Recently we demonstrated in neuroanatomical studies that substance P-immunoreactive neurons in the LH project the A7 area. To identify a functional connection between substance P neurons in the LH and the A7 cell group, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats and antinociception was obtained on the tail flick or foot withdrawal test. Cobalt chloride (100 nM) was then microinjected near the A7 cell group to block synaptic activation of spinally-projecting A7 neurons, which were identified using tyrosine-hydroxylase immunoreactivity. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the NK(1) receptor antagonist L-703-606 (5 microg) was microinjected near the A7 cell group following LH stimulation with carbachol. L-703-606 also abolished LH-induced antinociception. These results support the conclusion that antinociception produced by activating substance P neurons in the LH is mediated in part by the subsequent activation of spinally-projecting noradrenergic neurons in the A7 cell group.

The challenge of chronic pain

Chronic pain is a complex problem with staggering negative health and economic consequences. The complexity of chronic pain is presented within Cervero and Lairds model that describes three phases of pain, including pain without tissue damage, pain with tissue damage and inflammation, and neuropathic pain. The increased afferent input in phases 2 and 3 of chronic pain produces marked changes in primary afferents, dorsal root ganglia, and spinal cord dorsal horn. These changes promote the symptoms of chronic pain, including spontaneous pain, hyperalgesia, and allodynia. Increased afferent input also evokes supraspinal input to the dorsal horn, including biphasic innervation from the ventromedial medulla and A7 catecholamine cell group, that promotes hyperalgesia and allodynia. More rostral brain structures, such as the lateral hypothalamus, amygdala, and hippocampus, may also play a role in chronic pain. Although much has been discovered about the multiple pathological mechanisms involved in chronic pain, further research is needed to fully comprehend these mechanisms.

Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla.

Stimulation of the lateral hypothalamus (LH) produces antinociception modified by intrathecal serotonergic receptor antagonists. Spinally-projecting serotonergic neurons in the LH have not been identified, suggesting that the LH innervates brainstem serotonergic neurons in the rostral ventromedial medulla (RVM), known to modify nociception in the spinal cord dorsal horn. To determine whether substance P (SP) plays a role in LH-induced antinociception mediated by the RVM, we conducted an anatomical experiment using retrograde tract tracing combined with double label immunocytochemistry and found that neuron profiles immunoreactive for SP in the LH project to the RVM. To further identify a functional connection between SP neurons in the LH and the RVM, the cholinergic agonist carbachol (125 nmol) was microinjected into the LH of female Sprague-Dawley rats (250-350 g) and antinociception was obtained on the tail flick or foot withdrawal tests. Cobalt chloride (100 nM) was then microinjected in the RVM to block synaptic activation of spinally-projecting RVM neurons. Within 5 min of the cobalt chloride injection, the antinociceptive effect of carbachol stimulation was blocked. In another set of experiments, the specific NK1 receptor antagonist L-703,606 (5 microg) was microinjected in the RVM following LH stimulation with carbachol and abolished LH-induced antinociception as well. Microinjection of cobalt chloride or L-703,606 in the absence of LH stimulation had no effect. These anatomical and behavioral experiments provide converging evidence to support the hypothesis that antinociception produced by activating neurons in the LH is mediated in part by the subsequent activation of spinally-projecting neurons in the RVM.

The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain

The posterior hypothalamus (PH) is known to reduce nociceptive pain, but the effect of PH stimulation on neuropathic pain is not known. Because neurons containing the neurotransmitter orexin-A are located in the PH in some strains of rat and intrathecal injection of orexin-A produces antinociception in a neuropathic pain model, we hypothesized that orexin-A from neurons in the PH modifies nociception in the spinal cord dorsal horn. To test this hypothesis, the cholinergic agonist carbachol or normal saline was microinjected into the PH of lightly anesthetized female Sprague-Dawley rats with chronic constriction injury (CCI) and foot withdrawal latencies (FWL) were measured. Carbachol-induced PH stimulation produced dose dependent antinociception as shown by significantly increased FWL compared to saline controls. To investigate the role of orexin-A in PH-induced antinociception, the orexin-1 receptor antagonist SB-334867 or dimethyl sulfoxide (DMSO) for control, was given intrathecally following carbachol-induced PH stimulation. SB-334867 decreased FWL compared to DMSO controls. These data are suggestive that stimulating the PH produces antinociception in a neuropathic pain model and that the antinociceptive effect is mediated in part by orexin-1 receptors in the spinal cord dorsal horn.

The McGill Pain Questionnaire as a Multidimensional Measure in People with Cancer: An Integrative Review

First published in 1975, the McGill Pain Questionnaire (MPQ) is an often-cited pain measure, but there have been no systematic reviews of the MPQ in cancer populations. Our objective was to evaluate the MPQ as a multidimensional measure of pain in people with cancer. A systematic search of research that used the MPQ in adults with cancer and published in English from 1975 to 2009 was conducted. Twenty-one articles retrieved through computerized searches and nine studies from manual searches met the criteria. Review of the 30 studies demonstrated that pain intensity (n = 29 studies) and pain quality (n = 27 studies) were measured more frequently than pain location, pattern, and behavior parameters. Measuring cancer pain using the MPQ provided insights about disease sites, magnitude of pain, and effectiveness of treatment and intervention. Additionally, the MPQ data informed speculations about pain mechanisms, emotional status, overall sensory pain experience, changes in pain over time, and alleviating and aggravating behaviors/factors. Findings supported the MPQ as an effective multidimensional measure with good stability, content, construct, and criterion validity and showed sensitivity to treatment or known-group effects. The MPQ is a valid, reliable, and sensitive multidimensional measure of cancer pain. Cancer pain is a subjective complex experience consisting of multiple dimensions, and measuring cancer pain with the MPQ may help clinicians to more fully understand whether those dimensions of cancer pain influence each other. As a result, clinicians can provide better and effective cancer pain management.

Differences in pain location, intensity, and quality by pain pattern in outpatients with cancer

Background: Pain pattern represents how the individuals pain changes temporally with activities or other factors, but researchers have studied less the pattern of pain than its location, intensity, and quality parameters. Objective: The aim of this study was to explore differences in pain location, intensity, and quality by pattern groups in outpatients with cancer. Method: We conducted a comparative, secondary data analysis of data collected from 1994 to 2007. Seven hundred sixty-two outpatients with cancer completed the 0- to 10-point Pain Intensity Number Scale and the McGill Pain Questionnaire to measure pain location, quality and pattern. From all possible combinations of the 3 types of pain patterns, we created 7 pain pattern groups. Results: Pain pattern group distribution was as follows: pattern 1 (27%), 2 (24%), 3 (8%), 4 (12%), 5 (3%), 6 (18%), and 7 (8%). A significant higher proportion of patients with continuous pain pattern (patterns 1, 4, 5, and 7) reported pain location in 2 or more sites. Patients with patterns 1, 4, and 7 reported significantly higher worst pain mean scores than did patients with patterns 2, 3, and 6. Patients with pattern 7 reported significantly higher mean scores for the Pain Rating Index-sensory and total number of words selected than did patients with patterns 1, 2, 3, 4, and 6. Conclusions: Using pain pattern groups may help nurses to understand temporal changes in cancer pain and to provide more effective pain management, especially if the pain has a continuous component. Implications for Practice: Nurses or clinicians who are taking care of patients with cancer should recognize that pain patterns are associated with pain location, intensity, and quality.