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A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant upregulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as IL-1beta, IL-6, and IL-18. The obtained data provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.
Learn More >Potent opioid-based therapies are often unsuccessful in promoting satisfactory analgesia in neuropathic pain. Moreover, the side-effects associated with opioid therapy are still manifested in neuropathy-like diseases, including tolerance, abuse, addiction and hyperalgesia, although the mechanisms underlying these effects remain unclear. Studies in the spinal cord and periphery indicate that neuropathy alters the expression of mu-[MOR], delta-[DOR] or kappa-[KOR] opioid receptors, interfering with their activity. However, there is no consensus as to the supraspinal opioidergic modulation provoked by neuropathy, the structures where the sensory and affective-related pain components are processed. In this study we explored the effect of chronic constriction of the sciatic nerve over 7 and 30 days (CCI-7d and CCI-30d, respectively) on MOR, DOR and KOR mRNAs expression, using in situ hybridization, and the efficacy of G-protein stimulation by DAMGO, DPDPE and U-69593 (MOR, DOR and KOR specific agonists, respectively), using [35S]GTPγS binding, within opioid-sensitive brain structures. After CCI-7d, CCI-30d or both, opioid receptor mRNAs expression was altered throughout the brain: MOR – in the paracentral/centrolateral thalamic nuclei, ventral posteromedial thalamic nuclei, superior olivary complex, parabrachial nucleus and posterodorsal tegmental nucleus; DOR – in the somatosensory cortex [SSC], ventral tegmental area, caudate putamen [CPu], nucleus accumbens [NAcc], raphe magnus [RMg] and PB; and KOR – in the locus coeruleus. Agonist-stimulated [35S]GTPγS binding was altered following CCI: MOR – CPu and RMg; DOR – prefrontal cortex [PFC], SSC, RMg and NAcc; and KOR -PFC and SSC. Thus, this study shows that several opioidergic circuits in the brain are recruited and modified following neuropathy.
Learn More >To examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies.
Learn More >Chronic pain is common among older people with HIV. Etiologies of chronic pain are multifactorial in this population. A careful and thorough initial assessment of pain is important. Associated conditions that can contribute to pain should be explored and managed as indicated. Special consideration is warranted for some of the unique aspects of pain in people with HIV. Chronic pain management is multimodal; a variety of pharmacologic and nonpharmacologic strategies are effective. Among medications, opioids can be used but carry a risk of significant harms. The use and monitoring of opioids is discussed here, and recommendations are made for the safe prescribing of opioids for chronic pain.
Learn More >Ketamine, an anesthetic adjunct, is routinely administered as part of a balanced general anesthetic technique. We recently showed that the acute analgesic and dissociation properties of ketamine are separable to suggest that distinct neural circuits underlie these states.
Learn More >Cancer pain is often treated with opioids, a therapeutic regimen that can become a challenge in patients with an opioid use disorder (OUD). While use of the buprenorphine-naloxone combination is an effective medication-assisted treatment (MAT) for OUD, its use in pain patients with OUD has been controversial due to concerns that co-administration of buprenorphine can reduce or block analge-sia and precipitate opioid withdrawal in those patients requiring full opioid agonists. Data on its use in cancer pain patients are lack-ing. In this case series, the authors explore the frequency of buprenorphine-naloxone use and its outcomes in patients in a Compre-hensive Care Center (CCC) Pain Registry. OUD was deduced from an International Classification of Diseases (ICD-10) diagnostic code for opioid-related disorders recorded in the electronic medical records. Of 2,320 chronic cancer pain patients, 125 patients had ICD-10 code for opioid-related disorders, and 43 had a diagnosis of opioid abuse of whom 11 received buprenorphine-naloxone combina-tions. Eight patients on 18 (6-24) mg per day of buprenorphine-naloxone remained in therapy for 4 (2-7) years without opioid abuse relapse. This assessment was based on clinician's notes, the Prescription Monitoring Program, random urine drug screening, and the absence of Urgent Care Center visits for opioid withdrawal or overdose. When short-term opioids were administered for acute pain, these patients were able to taper down and stop them quickly without an opioid abuse relapse. Buprenorphine-naloxone was effec-tive as the sole analgesic in selected patients. Given its success at the CCC, buprenorphine-naloxone should be made available and strongly considered as a treatment for patients suffering from OUD during and following cancer treatment and when cancer pain re-duces or resolves.
Learn More >To test for the possible antinociceptive effect of nifedipine in rodent models of acute and chronic neuropathic orofacial pain and the possible involvement of TRP- and NMDA-related processes in this effect.
Learn More >We aimed to assess the safety of opioids in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.
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