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Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CBR), with CBR desensitization occurring via phosphorylation of CBRs by a G protein-coupled receptor kinase and subsequent association with an arrestin protein. Previous studies have shown that (1) desensitization-resistant S426A/S430A mice exhibit a modest delay in tolerance for Δ-THC and CP55,940 but a more pronounced disruption in tolerance for WIN 55,212-2 and (2) that c-Jun N-terminal kinase (JNK) signaling may selectively mediate antinociceptive tolerance to morphine compared to other opioid analgesics. In the current study, we found that pretreatment with the JNK inhibitor SP600125 (3 mg/kg) attenuates tolerance to the antinociceptive and anti-allodynic effects of Δ-THC (6 mg/kg) in wild-type mice using the formalin test and in mice with cisplatin-evoked neuropathic pain, respectively. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Δ-THC (30 mg/kg) but not WIN 55,212-2 (10 mg/kg) in the tail-flick assay using S426A/S430A mice. Interestingly, SP600125 pretreatment accelerated tolerance to the antinociceptive and anti-allodynic effects of CP55,940 (0.3 mg/kg) in mice with acute and neuropathic pain. These results demonstrate that inhibition of JNK signaling pathways delay tolerance to Δ-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.
Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses, thus targeted treatment is highly warranted. Evidence supporting graded in-vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses (MLM). Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up over 80% of participants had improved across all primary and secondary outcomes. MLM results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All five outcomes emerged as significantly improved at 3- and 6-month follow-up. The results of this replicated SCED support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance.
Valid and efficient assessment of patient-reported outcomes remains a priority to guide pain treatment and research. PROMIS® pediatric self-report and parent-proxy measures offer feasible and rigorous evaluation of functioning in children with chronic conditions, including pain. A key challenge is determining the usefulness of multisource information from children and caregivers for understanding pain and function. Our primary aim examined child-caregiver agreement across child functioning domains. Our secondary aim examined child and caregiver factors associated with child-caregiver agreement.
Chronic pain is a multidimensional experience associated with psychosocial (e.g., pain-related beliefs and pain coping responses) and spiritual factors. Spirituality is a universal aspect of the human experience that has been hypothesized to impact pain experience via its effects on pain, physical/psychological function, resilience and pain-related beliefs, and pain coping responses. However, research evaluating the associations between measures of spirituality and measures of pain and function in individuals with chronic pain is limited. This study seeks to address this limitation.
Knee OA is a leading global cause of morbidity. This study investigates the effects of knee SF from patients with OA on the activity of dorsal root ganglion sensory neurons that innervate the knee (knee neurons) as a novel translational model of disease-mediated nociception in human OA.
The popular herbal medicine, St. John's wort, is a potent inducer of several cytochrome P450 enzymes, including CYP3A4, which plays a role in the metabolism of fentanyl. St. John's wort may also influence the expression of P-glycoprotein, which can alter the movement of drugs across the blood-brain barrier.
Persons with chronic musculoskeletal pain may be hypervigilant for pain-related cues which, paradoxically, may be maintaining their pain. Several randomized controlled trials have assessed whether a modified dot-probe protocol (i.e., attention bias modification; ABM) reduces chronic pain- and pain-related symptoms in persons with several diagnoses, including fibromyalgia. Scalability and economic efficiency potentiates the appeal of ABM protocols; however, research results have been mixed, with only some studies evidencing significant symptom gains from ABM and some evidencing gains for the control group. The current randomized controlled trial sought to replicate and extend previous ABM research using idiosyncratic word stimuli and a 1-month follow-up. Participants included treatment-seeking adult women (n=117) with fibromyalgia who were randomly assigned to a standard (i.e., control) or active (i.e., ABM) condition. The protocol was delivered online and involved twice-weekly 15-min sessions, for 4 weeks, with questionnaires completed at baseline, post-treatment, and 1-month follow-up. Symptom reports were analysed with mixed hierarchical modelling. There was no evidence of differences between the control and ABM groups. Both groups had small significant (ps<.05) improvements in pain experiences at post-treatment, but not at follow-up (ps>.05). There were no significant changes for either group on measures of anxiety sensitivity, illness/injury sensitivity, pain-related fear, pain-related anxiety, or attentional biases (ps>.05). The current findings add to the emerging and mixed literature regarding ABM for pain by demonstrating that ABM produces no substantive improvements in pain or pain-related constructs in a large sample of patients with fibromyalgia.