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Affective disorders are common comorbidities of chronic inflammatory pain that are often overlooked in primary care. As the impact of inflammatory pain upon mood-like disorders in animal models is not well known, our objective was to assess whether prolonged experimental monoarthritis (ARTH) induced the development of anxiety and depressive-like behaviours in rodents and if amitriptyline, an antidepressant commonly used in the treatment of chronic pain, could reverse both nociceptive and mood-like impairments. Experimental ARTH was induced through an injection of kaolin/carrageenan into the right knee joint with control (SHAM) animals injected with saline. Four weeks after induction, ARTH animals displayed mechanical hyperalgesia and a depressive-like phenotype as they showed a significant increase in immobility and a decrease in the latency to immobility in the forced-swimming test at the expense of the time spent climbing/swimming. ARTH animals also displayed a decreased sucrose preference, an index of anhedonia and anxiety-like behaviour as time spent exploring the open arms of the elevated-plus-maze was decreased when compared to controls. The anxiety-like phenotype was also supported by an increase in the number of fecal boli left in the open field. In ARTH animals, the administration of amitriptyline decreased mechanical hyperalgesia and increased sucrose preference and the time spent climbing, although it had a deleterious effect in the performance of control animals. Our data show that this model of ARTH can be useful for the study of chronic pain-mood disorders comorbidities and that amitriptyline is able to partly reverse the associated nociceptive and emotional impairments.

The involvement of the prefrontal cortex in pain processing has been recently addressed. We studied the role of the infralimbic cortex (IL) and group I metabotropic glutamate receptors (mGluRs) in descending modulation of nociception in control and monoarthritic (ARTH) conditions. Nociception was assessed using heat-induced paw withdrawal while drugs were microinjected in the IL of rats. Local anesthesia of the IL or the adjacent prelimbic cortex (PL) facilitated nociception, indicating that IL and PL are tonically promoting spinal antinociception. Phasic activation with glutamate (GLU) revealed opposing roles of the PL and IL; GLU in the PL had a fast antinociceptive action, while in the IL it had a slow onset pronociceptive action. IL administration of a local anesthetic or GLU produced identical results in ARTH and control animals. An mGluR5 agonist in the IL induced a pronociceptive effect in both groups, while mGluR5 antagonists had no effect in controls but induced antinociception in ARTH rats. Activation of the IL mGluR1 (through co-administration of mGluR1/5 agonist and mGluR5 antagonist) did not alter nociception in controls but induced antinociception in ARTH animals. IL administration of an mGluR1 antagonist failed to alter nociception in either experimental group. Finally, mGluR5 but not mGluR1 antagonists blocked the pronociceptive action of GLU in both groups. The results indicate that IL contributes to descending modulation of nociception. mGluR5 in the IL enhance nociception in healthy control and monoarthritic animals, an effect that is tonic in ARTH. Moreover, activation of IL mGluR1s attenuates nociception following the development of monoarthritis.

Objectives Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular damage and chronic pain, with a prevalence of up to 50% in individuals >60 years of age. Patients suffering from chronic painful conditions, including OA, also frequently report anxiety or depression. A systematic review and meta-analysis were performed to assess the correlation between pain severity and depressive and anxious symptomatology in OA patients. Methods A systematic search was conducted using four databases (PubMed, Medline, Scopus, and Web of Science) from inception up to 14th January of 2020. We included original articles evaluating pain severity and anxiety and/or depression severity in OA-diagnosed patients. Detailed data were extracted from each study, including patients’ characteristics and pain, anxiety, and depression severity. When available, the Pearson correlation coefficient between pain and depression severity and pain and anxiety severity was collected and a meta-analysis of random effects was applied. Results This systematic review included 121 studies, with a total of 38085 participants. The mean age was 64.3 years old and subjects were predominantly female (63%). The most used scale to evaluate pain severity was the Western Ontario and the McMaster Universities Osteoarthritis Index, while for anxiety and depression, the Hospital Anxiety and Depression Scale was the most used. The meta-analysis showed a moderate positive correlation between pain severity and both anxious (r = 0.31, p < 0.001) and depressive symptomatology (r = 0.36, p < 0.001). Conclusions Our results demonstrate a significant correlation between pain and depression/anxiety severity in OA patients, highlighting the need for its routine evaluation by clinicians.

The dorsomedial nucleus of the hypothalamus (DMH) has been proposed to participate in stress-induced hyperalgesia through facilitation of pronociceptive cells in the rostroventromedial medulla (RVM). We hypothesized that the DMH participates in hyperalgesia induced by arthritis. The DMH was pharmacologically manipulated while assessing heat-evoked nociceptive behavior or the discharge rates of pronociceptive RVM ON- and antinociceptive RVM OFF-like cells in NAIVE, SHAM and monoarthritic (ARTH) animals. In NAIVE and SHAM animals, the changes in nociceptive behavior induced by activation of the DMH by glutamate and inhibition by lidocaine were in line with earlier evidence indicating that the DMH has a nociceptive facilitating role. However, in ARTH animals, neither activation nor inhibition of the DMH influenced pain-like behavior evoked by stimulation of an uninflamed skin region (paw and tail). In accordance with these behavioral results, activation or inhibition of the DMH induced pronociceptive changes in the discharge rates of RVM cells in NAIVE and SHAM animals, which suggests that the DMH has a pronociceptive role mediated by the RVM in normal animals. However, in ARTH animals, both glutamate and lidocaine in the DMH failed to influence either pain-like behavior or noxious stimulation-evoked responses of RVM cells, while blocking the DMH increased spontaneous activity in the pronociceptive RVM ON cells. Our data indicate that the DMH participates in descending facilitation of cutaneous nociception in healthy controls, but it is not engaged in the regulation of cutaneous nociception in monoarthritic animals, while a minor role in tonic suppression of nociception in arthritis cannot be discarded.

Transient receptor potential ankyrin 1 (TRPA1) channel antagonists have suppressed mechanical hypersensitivity in peripheral neuropathy, while their effect on ongoing neuropathic pain is not yet known. Here, we assessed whether blocking the TRPA1 channel induces place-preference, an index for the relief of ongoing pain, in two experimental rat models of peripheral neuropathy. Diabetic neuropathy was induced by streptozotocin and spared nerve injury (SNI) model of neuropathy by ligation of two sciatic nerve branches. Conditioned place-preference (CPP) paradigm involved pairing of the drug treatment with one of the chambers of a CPP device once or four times, and the time spent in each chamber was recorded after conditioning sessions to reveal place-preference. The mechanical antihypersensitivity effect was assessed by the monofilament test immediately after the conditioning sessions. Intraperitoneally (30mg/kg; diabetic and SNI model) or intrathecally (10μg; diabetic model) administered Chembridge-5861528 (CHEM) was used as a selective TRPA1 channel antagonist. In diabetic and SNI models of neuropathy, CHEM failed to induce CPP at a dose that significantly attenuated mechanical hypersensitivity, independent of the route of drug administration or number of successive conditioning sessions. Intrathecal clonidine (an α2-adrenoceptor agonist; 10μg), in contrast, induced CPP in SNI but not control animals. The results indicate that ongoing pain, as revealed by CPP, is less sensitive to treatment by the TRPA1 channel antagonist than mechanical hypersensitivity in peripheral neuropathy.

IntroductionIn chronic pain disorders, galanin (GAL) is able to either facilitate or inhibit nociception in the spinal cord but the contribution of supraspinal galanin to pain signalling is mostly unknown. The dorsomedial nucleus of the hypothalamus (DMH) is rich in galanin receptors (GALR) and is involved in behavioural hyperalgesia. In this study, we evaluated the contribution of supraspinal GAL to behavioural hyperalgesia in experimental monoarthritis.MethodsIn Wistar-Han males with a four week kaolin/carrageenan-induced monoarthritis (ARTH), paw-withdrawal latency (PWL) was assessed before and after DMH administration of exogenous GAL, a non-specific GALR antagonist (M40), a specific GALR1 agonist (M617) and a specific GALR2 antagonist (M871). Additionally, the analysis of c-Fos expression after GAL injection in the DMH was used to investigate the potential involvement of brainstem pain control centres. Finally, electrophysiological recordings were performed to evaluate whether pronociceptive On- or antinociceptive Off-like cells in the rostral ventromedial medulla (RVM) relay the effect of GAL.ResultsExogenous GAL in the DMH decreased PWL in ARTH and SHAM animals, an effect that was mimicked by a GALR1 agonist (M617). In SHAM animals, an unselective GALR antagonist (M40) increased PWL, while a GALR2 antagonist (M871) decreased PWL. M40 or M871 failed to influence PWL in ARTH animals. Exogenous GAL increased c-Fos expression in the RVM and dorsal raphe nucleus (DRN), with effects being more prominent in SHAM than ARTH animals. Exogenous GAL failed to influence activity of RVM On- or Off-like cells of SHAM and ARTH animals.ConclusionsOverall, exogenous GAL in the DMH had a pronociceptive effect that is mediated by GALR1 in healthy and arthritic animals and is associated with alterations of c-Fos expression in RVM and DRN that are serotonergic brainstem nuclei known to be involved in the regulation of pain.

A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.