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Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2 mg monoiodoacetate (MIA), respectively. Capsaicin (30–100 μg/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30 μg and reached its maximal level at 100 μg. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10 mg/kg). The oral administrations of pregabalin (10 mg/kg) and celecoxib (3 mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway.

Pain per se may increase anxiety and conversely, anxiety may increase pain. Therefore, a positive feedback loop between anxiety and pain possibly contributes to pain and suffering in some pathophysiological pain conditions, such as that induced by peripheral nerve injury. Recent results indicate that transient receptor channels 4 and 5 (TRPC4/C5) in the amygdala have anxiogenic effects in rodents, while their role in chronic pain conditions is not known. Here, we studied whether the amygdaloid TRPC4/C5 that are known to have anxiogenic properties contribute to the maintenance of sensory or affective aspects of pain in an experimental model of peripheral neuropathy. Rats with a spared nerve injury (SNI) model of neuropathy in the left hind limb had a chronic cannula for microinjections of drugs into the right amygdala or the internal capsule (a control site). Sensory pain was assessed by determining mechanical hypersensitivity with calibrated monofilaments and affective pain by determining aversive place-conditioning. Amygdaloid treatment with ML-204, a TRPC4/C5 antagonist, produced a dose-related (5-10 mu g) antihypersensitivity effect, without obvious side-effects. Additionally, amygdaloid administration of ML-204 reduced affective-like pain behavior. In the internal capsule, ML-204 had no effect on hypersensitivity or affective-like pain in SNI animals. In healthy controls, amygdaloid administration of ML-204 failed to influence pain behavior induced by mechanical stimulation or noxious heat. The results indicate that the amygdaloid TRPC4/C5 contribute to maintenance of pain hypersensitivity and pain affect in neuropathy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Although research on DNIC has revealed the inhibitory effect occurring between two remote pain stimuli, the interrelation between two adjacent painful stimuli has not yet been characterized. In the present study, we used a sample of 40 healthy volunteers to examine the effect of 30-s immersion of the fingers in water of 1 degree C, as a conditioning stimulus, on pain intensities produced by conditioned mechanical punctuate stimuli, applied both adjacent and contralateral to the cooled area. There was a significant decrease in mechanical pain intensities from 17.23+/-2.39 at baseline to 12.45+/-2.39 when stimulating immediately after the cold immersion at an adjacent site, and from 20.00+/-2.39 to 15.08+/-2.39 at remote sites (F=20.02, p0.0001). A significant positive correlation between the extent of pain reduction in the cooled and in the uncooled hand was found (r(s)=0.59, p=0.0001). The extent of pain reduction following cooling in the cooled and in the uncooled hand was also found to be similar for males and for females (p=0.63). It is concluded that under the conditions of this experiment, EA affects heterotopic and homotopic regions similarly and without gender differences.

Single-unit recording techniques were used to investigate spinal cord neurons likely to be involved in low back pain. Most dorsal horn neurons with somatic receptive fields in the low back region have complex receptive fields involving deep and superficial tissues. This report shows, for the first time, that activity in some nocireceptive 'low back' neurons is suppressed by somatic stimulation of discrete sites within the larger excitatory receptive field. Both weak and intense mechanical stimulation of skin or deep tissues suppressed activity in some neurons. The neurons in this population tested for rostral projections had long ascending axons.

We have investigated the effects of intrathecal (i.t.) N- methyl- d -aspartate (NMDA) and an NMDA antagonist d -2-amino-5-phosphonovalerate (APV) on spontaneous and evoked activity in rat dorsal horn convergent neurones. Extracellular recordings were made from 54 convergent neurones located in both the superficial and deep dorsal horn. NMDA induced a dose-dependent increase in the spontaneous firing rate of convergent neurones, with 1 μM and 1 mM NMDA producing firing rates significantly greater than i.t. saline. In addition, NMDA induced hyperexcitability to subsequent noxious mechanical stimuli at 1 μM and 1 mM, and to innocuous stimuli at 1 mM. The NMDA-induced spontaneous hyperexcitability was reversed by pretreatment with 1 μM APV i.t. Diffuse noxious inhibitory controls (DNIC) applied to areas of the body remote from the receptive field also inhibited the NMDA-induced effects. There was no difference between the responses of superficial and deep dorsal horn neurones, suggesting a uniform excitatory action of NMDA on convergent neurones. Our results support a role for the NMDA receptor in mediating a central component of hyperalgesia, at the level of the spinal cord dorsal horn.

Previous work suggested that pain of distinct tissue origins was differentially represented in the midbrain periaqueductal gray (PAG). That is, persistent pain of deep origin (muscle, joint viscera) "activated" ventrolateral PAG neurons and triggered quiescence, hyporeactivity and vasodepression (i.e. passive emotional coping); whereas intermittent cutaneous pain "activated" lateral PAG neurons and triggered fight-flight (i.e. active emotional coping). Cutaneous noxious stimuli, if inescapable however, trigger a passive emotional coping reaction similar to that evoked by pain of deep origin. This raised the question--is it the behavioural significance (escapability versus inescapability) or the tissue origin (cutaneous versus deep) of the pain, that is represented in the PAG? In this study we used immediate-early-gene (c-Fos) expression to examine PAG and spinal activation patterns following "inescapable" (persistent) pain of cutaneous versus deep origin. It was found that selective activation of the ventrolateral PAG and passive emotional coping were evoked by an inescapable cutaneous noxious stimulus (i.e. clip of the neck), as well as by a deep noxious stimulus (i.e. neck muscle pain). In the upper cervical spinal cord, however, these noxious manipulations evoked distinct patterns of Fos expression which reflected the different patterns of primary afferent termination arising from skin versus muscle. The results suggest that whereas pain representation in the spinal cord accurately reflects tissue origin, pain representation in the PAG better reflects behavioural significance.

The development of diffuse noxious inhibitory controls (DNIC) was studied in postnatal rats aged 12, 21 and 42-days-old, using immunoreactive localization of the c-fos protein products induced in the dorsal horn by noxious stimulation. The presence of DNIC was revealed by the reduction in the levels of Fos-like immunoreactivity that are normally induced by a standardized primary pinch stimulus when this stimulus was accompanied by a concurrent noxious stimulus (formalin) to a heterotopic body part. Significant reductions were seen at postnatal day 42 (P42; 15% reduction) and P21 (17% reduction), but concurrent stimulation had no significant effect at P12. These results suggest that the system subserving DNIC is functionally mature by P21, but not effective at P12. This delayed maturation of an inhibitory system may underlie the extreme sensitivity to somatosensory stimulation seen in neonatal pups and premature infants.

Responses of dorsal horn neurons to iontophoretic application of substance P (80–120 nA), and to noxious thermal and noxious mechanical stimulations of the receptive field in the hind limb were tested in adult cats before and after the administration of the specific, non-peptide, NK-1 receptor antagonist CP-96,345 (0.5 mg/kg, i.v.). CP-96,345 inhibited the response of the neurones to substance P and also the response of these substance P-sensitive neurones to noxious thermal stimulation. The response of the substance P-insensitive neurones to noxious heat stimulations were, however, unaffected by CP-96,345. The effect of CP-96,345 on the response of neurones to noxious mechanical stimulation was variable. The results confirm the role of substance P in thermal nociception.

In chloralose-anaesthetized or decerebrate cats intra-arterially administered bradykinin (BKN) and noxious radiant heat were tested on dorsal horn neurones characterized according to their responses to natural stimuli. Of the 28 neurones which were excited only to non-noxious forms of stimuli, BKN affected 4 while noxious radiant heat was ineffective. BKN also affected relatively few of the nociceptor-driven neurones (18 of 60) and most of these were inhibited, while noxious radiant heat excited the majority of these cells (47 of 60). Therefore, under our experimental conditions, noxious radiant heat would appear to be a more effective and specific noxious stimulus than BKN.

Extracellular recordings of single convergent dorsal horn neurones in the spinal cord region L1-L3 were made in rats anaesthetised with halothane in a gaseous mix of N2O and O2. Subcutaneous formalin (5%, 50 microliters) has previously been found to produce a prolonged distinct biphasic response of dorsal horn convergent neurones in the same preparation. The present study demonstrates that the second period of neuronal excitation which occurs at about 20 min and lasts for at least another 40 min, could be abolished by lignocaine (2%, 50 microliters) injected into the site of the formalin injection (n = 5). The inhibition of formalin-evoked activity lasted for about 10-20 min and was followed by complete recovery of the neuronal response. The same dose of i.v. lignocaine had no effect on the formalin-induced neuronal activity (n = 4). Profound inhibitions of the second phase were also produced by tactile segmental stimulation and noxious stimuli applied to widespread areas of the body (diffuse noxious inhibitory controls). These findings are discussed with regard to the peripheral and central consequences of prolonged noxious stimuli.